Hemodialyzer for blood purification

ABSTRACT

The present disclosure relates to a dialyzer comprising a bundle of semipermeable hollow fiber membranes which is suitable for blood purification, wherein the dialyzer has an increased ability to remove larger molecules while at the same time it is able to effectively remove small uremic toxins and efficiently retain albumin and larger proteins. The invention also relates to using said dialyzer in hemodialysis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/851,439, filed on Apr. 17, 2020, which is acontinuation application of U.S. patent application Ser. No. 15/115,951,filed on Aug. 2, 2016, which is the U.S. national phase ofPCT/EP2015/052365, filed on Feb. 5, 2015, which claims priority toEuropean Patent Application 14154172.2, filed on Feb. 6, 2014. Thedisclosures of U.S. patent application Ser. No. 16/851,439, U.S. patentapplication Ser. No. 15/115,951, European Patent Application 14154172.2,and PCT/EP2015/052365 are hereby incorporated herein by reference intheir entireties.

TECHNICAL FIELD

The present disclosure relates to a dialyzer comprising a bundle ofsemipermeable hollow fiber membranes which is suitable for bloodpurification, wherein the dialyzer has an increased ability to removelarger molecules while at the same time it is able to effectively removesmall uremic toxins and efficiently retain albumin and larger proteins.The invention also relates to using said dialyzer in hemodialysis.

DESCRIPTION OF THE RELATED ART

Capillary dialyzers are widely used for blood purification in patientssuffering from renal insufficiency, i.e., for treatment of the patientsby hemodialysis, hemodiafiltration or hemofiltration.

The devices generally consist of a casing comprising a tubular sectionwith end caps capping the mouths of the tubular section. A bundle ofhollow fiber membranes is arranged in the casing in a way that a seal isprovided between the first flow space formed by the fiber cavities and asecond flow space surrounding the membranes on the outside. Examples ofsuch devices are disclosed in EP 0 844 015 A2, EP 0 305 687 A1, and WO01/60477 A2.

Module performance is controlled by membrane properties and masstransfer boundary layers that develop in the fluid adjacent to themembrane surface in the lumen and the shell. Boundary layer resistancesare significant in many processes including dialysis.

Accordingly, the most important factor influencing performance of thedevice is the hollow fiber membrane which is used for accomplishing thedevice. Dialysis membranes today are designed to allow for the removalof uremic toxins and excess water from the blood of patients withchronic renal failure while balancing the electrolyte content in theblood with the dialysis fluid. Uremic toxins can be classified accordingto their size as shown in FIG. 1 or as described in Vanholder et al.:“Review on uremic toxins: Classification, concentration, andinterindividual variability”, Kidney Int. (2003) 63, 1934-1943, and/oraccording to their physicochemical characteristics in smallwater-soluble compounds (e.g., urea and creatinine), protein-boundsolutes (e.g., p-cresyl sulfate) and middle molecules (e.g.,b2-microglobulin and interleukin-6). While the removal of smallmolecules takes place mainly by diffusion due to concentrationdifferences between the blood stream and the dialysis fluid flow, theremoval of middle molecules is mainly achieved by convection throughultrafiltration. The degree of diffusion and convection depends on thetreatment mode (hemodialysis, hemofiltration or hemodiafiltration) aswell as on the currently available membrane type (low-flux high-flux,protein leaking, or high cut-off membranes).

Another important factor influencing performance of the device dependsstrongly on the geometry of the housing and the fiber bundle locatedtherein, including the geometry of the single hollow fibers. Relevantparameters as concerns the fibers are, apart from their specificmembrane structure, composition and related performance the effective(accessible) length of the fibers, the inner diameter and the wallthickness of the fibers and their overall three-dimensional geometry.The aforementioned concentration and thermal boundary layers adjacent tothe fiber surface as well as uniformity of the flow through a dialyzerwill otherwise be influenced by the packing density and/or the crimpingof the single hollow fibers. Crimping or undulation transforms astraight fiber into a generally wavy fiber. Crimped fibers overcomeproblems of uniformity of flow around and between the fibers and oflongitudinal fiber contact which can reduce the fiber surface areaavailable for mass transfer by reducing said longitudinal contactbetween adjacent fibers, thereby improving flow uniformity and access tomembrane area. The performance of dialyzers is related also to themembrane packing density which in turn is closely connected to the flowcharacteristics. A high membrane packing density increases theperformance of the device as long as the uniformity of the flow is notaffected. This can be achieved by introducing, into the housing, fiberbundles with fibers that are at least partially crimped. For example, EP1 257 333 A1 discloses a filter device, preferably for hemodialysis,that consists of a cylindrical filter housing and a bundle of hollowfibers arranged in the filter housing, wherein all of the hollow fibersare crimped, resulting in a wavelength and amplitude which follow acertain geometrical principle wherein also fibers length, outer fiberdiameter and the diameter of the fiber bundle play some role. Thepacking density of the fibers within the housing is in the range of from60.5 to 70%, relative to the usable cross-section area of the housingwhich is calculated by multiplying the cross-section area by 0.907. EP 2815 807 A1 refers to dialyzers comprising crimped fibers, wherein only aspecific portion of the fibers is crimped, which leads to some furtherimprovements of the filter performance.

The sieving property of a membrane, i.e. its permeability to solutes, isdetermined by the pore size and sets the maximum size for the solutesthat can be dragged through the membrane with the fluid flow. Thesieving coefficient for a given substance could be simply described asthe ratio between the substance concentration in the filtrate and itsconcentration in the feed (i.e., the blood or plasma), and is thereforea value between 0 and 1. Assuming that the size of a solute isproportional to its molecular weight, a common way to illustrate theproperties of membranes is by building a sieving curve, which depictsthe sieving coefficient as a function of the molecular weight. Theexpression “molecular weight cut-off” or “MWCO” or “nominal molecularweight cut-off” as interchangeably used herein is a value for describingthe retention capabilities of a membrane and refers to the molecularmass of a solute where the membranes have a rejection of 90%,corresponding to a sieving coefficient of 0.1. The MWCO canalternatively be described as the molecular mass of a solute, such as,for example, dextrans or proteins where the membranes allow passage of10% of the molecules. The shape of the curve depends, to a significantextent, on the pore size distribution and to the physical form ofappearance of the membrane and its pore structure, which can otherwisebe only inadequately described. Sieving coefficients therefore are agood description not only of the performance of a membrane but are alsodescriptive of the specific submacroscopic structure of the membrane.

In vitro characterization of blood purification membranes includes thedetermination of the removal rate for small and middle molecules as wellas for albumin. For this purpose, filtration experiments are carried outwith different marker solutes, among which dextran has been widely usedsince it is non-toxic, stable, inert and available in a wide range ofmolecular weights (Michaels A S. Analysis and Prediction of SievingCurves for Ultrafiltration Membranes: A Universal Correlation? Sep SciTechnol. 1980; 15(6):1305-1322. Leypoldt J K, Cheung A K.Characterization of molecular transport in artificial kidneys. ArtifOrgans. 1996; 20(5):381-389). Since dextrans are approximately linearchains, their size does not correspond to that of a protein with similarmolecular weight. However, comparisons are possible once the radius ofthe dextran coiled chain is calculated. The sieving curve determined fora polydisperse dextran mixture can thus be considered a standardcharacterization technique for a membrane, and a number of recentpublications have analyzed this methodology (Bakhshayeshi M, Kanani D M,Mehta A, et al. Dextran sieving test for characterization of virusfiltration membranes. J Membr Sci. 2011; 379(1-2):239-248. BakhshayeshiM, Zhou H, Olsen C, Yuan W, Zydney A L. Understanding dextran retentiondata for hollow fiber ultrafiltration membranes. J Membr Sci. 2011;385-386(1):243-250. Hwang K J, Sz PY. Effect of membrane pore size onthe performance of cross-flow microfiltration of BSA/dextran mixtures. JMembr Sci. 2011; 378(1-2):272-279. 11. Peeva P D, Million N, Ulbricht M.Factors affecting the sieving behavior of anti-fouling thin-layercross-linked hydrogel polyethersulfone composite ultrafiltrationmembranes. J Membr Sci. 2012; 390-391:99-112. Boschetti-de-Fierro A etal. Extended characterization of a new class of membranes for bloodpurification: The high cut-off membranes. Int J Artif Organs 2013;36(7), 455-463).

Conventional dialysis membranes are classified as low-flux or high-flux,depending on their permeability. A third group, called protein leakingmembranes, is also available on some markets. These three membranegroups were described in a review by Ward in 2005 (Ward R A.Protein-leaking membranes for hemodialysis: a new class of membranes insearch of an application? J Am Soc Nephrol. 2005; 16(8):2421-2430).High-flux membranes used in devices, such as, for example, Polyflux®170H (Gambro), Revaclear® (Gambro), Ultraflux® EMIC2 (Fresenius MedicalCare), Optiflux® F180NR (Fresenius Medical Care) have been on the marketfor several years now. The high-flux membranes used therein are mainlypolysulfone or polyethersulfone based membranes and methods for theirproduction have been described, for example, in U.S. Pat. No. 5,891,338and EP 2 113 298 A1. Another known membrane is used in the Phylther® HF17G filter from Bellco Societá unipersonale a r.l. It is generallyreferred to as high-flux membrane and is based on polyphenylene. Inpolysulfone or polyethersulfone based membranes, the polymer solutionoften comprises between 10 and 20 weight-% of polyethersulfone orpolysulfone as hydrophobic polymer and 2 to 11 weight-% of a hydrophilicpolymer, in most cases PVP, wherein said PVP generally consists of a lowand a high molecular PVP component. The resulting high-flux typemembranes generally consist of 80-99% by weight of said hydrophobicpolymer and 1-20% by weight of said hydrophilic polymer. Duringproduction of the membrane the temperature of the spinneret generally isin the range of from 25-55° C. Polymer combinations, process parametersand performance data can otherwise be retrieved from the referencesmentioned or can be taken from publicly available data sheets. Theexpression “high-flux membrane(s)” as used herein refers to membraneshaving a MWRO between 5 kDa and 10 kDa and a MWCO between 25 kDa and 65kDa, as determined by dextran sieving measurements according toBoschetti-de-Fierro et al. (2013). The average pore radius is in therange of from 3.5 to 5.5 nm, wherein the pore size is determined fromthe MWCO based on dextran sieving coefficients according toBoschetti-de-Fierro et al. (2013) and Granath et al. (1967). Molecularweight distribution analysis by gel chromatography on sephadex. JChromatogr A. 1967; 28(C):69-81. The main difference between high-fluxmembranes and low-flux membranes is a higher water permeability and theability to remove small-to-middle molecules like β2-microglobulin.

High-flux membranes are also contained in current filter devices whichcan be used or have been explicitly designed for use inhemodiafiltration, for example the commercially available productsNephros OLpūr™ MD 190 or MD 220 (Nephros Inc., USA) or theFX_(CorDiax)600, FX_(CorDiax)800 or FFX_(CorDiax)1000 filters (FreseniusMedical Care Deutschland GmbH). While hemodialysis (HD) is primarilybased on diffusion, thus relying on differences in concentration as thedriving force for removing unwanted substances from blood,hemodiafiltration (HDF) also makes use of convective forces in additionto the diffusive driving force used in HD. Said convection isaccomplished by creating a positive pressure gradient across thedialyzer membrane. Accordingly, blood is pumped through the bloodcompartment of the dialyzer at a high rate of ultrafiltration, so thereis a high rate of movement of plasma water from blood to dialysate whichmust be replaced by substitution fluid that is infused directly into theblood line. Dialysis solution is also run through the dialysatecompartment of the dialyzer. Hemodiafiltration is used because it mayresult in good removal of both large and small molecular weight solutes.The substitution fluid may be prepared on-line from dialysis solutionwherein the dialysis solution is purified by passage through a set ofmembranes before infusing it directly into the blood line. There arestill some concerns as regards the on-line creation of substitutionfluid because of potential impurities in the fluid. Other concerns arerelated to the fact that HDF therapy requires a high blood flow and acorresponding access and patients who tolerate such high flows. However,a considerable number of patients are older, diabetic and/or with a poorvascular access; in this situation high blood flows are more difficultto get at the expense of lower postdilution exchange volumes, thuslimiting the usability and/or benefit of HDF treatment. Especially forthese patients it would be extremely desirable to achieve an at leastequally good removal of both large and small molecular weight solutesalso with hemodialysis, which so far is not feasible.

Protein leaking membranes, another class of membranes which should bementioned here, have a water permeability similar to that of low-fluxmembranes, the ability to remove small-to-middle molecules similar tohigh-flux membranes, and they show albumin loss which is generallyhigher than that of high-flux membranes. Their use in HDF application istherefore not advisable because especially in convective procedures,such as hemodiafiltration, their albumin leakage is too high.

Lately a fourth type has emerged, called high cut-off membranes, whichform a new group in addition to the ones mentioned before. This type ofmembrane has first been disclosed in WO 2004/056460 A1 wherein certainearly high cut-off membranes are described which were primarily intendedfor the treatment of sepsis by eliminating sepsisassociated inflammatorymediators. Advanced dialyzers making use of high cut-off type membraneswhich are currently on the market are, for example, HCO1100®, septeX™and Theralite®, all available from Gambro Lundia AB. Known uses of saidadvanced high cut-off membranes include treatment of sepsis (EP 2 281625 A1), chronic inflammation (EP 2 161 072 A1), amyloidosis andrhabdomyolysis and treatment of anemia (US 2012/0305487 A1), the mostexplored therapy to date being the treatment of myeloma kidney patients(U.S. Pat. No. 7,875,183 B2). Due to the loss of up to 40 g of albuminper standard treatment, high cut-off membranes so far have been used foracute applications only, although some physicians have contemplatedbenefits of using them in chronic applications, possibly in conjunctionwith albumin substitution and/or in addition to or in alternate orderwith standard high-flux dialyzers. The expression “high cut-offmembrane” or “high cut-off membranes” as used herein refers to membraneshaving a MWRO of between 15 and 20 kDa and a MWCO of between 170-320kDa. The membranes can also be characterized by a pore radius, on theselective layer surface of the membrane, of between 8-12 nm. For theavoidance of doubt, the determination of MWRO and MWCO for a givenmembrane and as used herein is according to the methods ofBoschetti-de-Fierro et al. (2013); see “Materials and Methods”section ofthe reference and Example 3 of this description. Accordingly, theexpressions “as determined by dextran sieving” or “based on dextransieving” also refer to the dextran sieving method as described inBoschetti-de-Fierro et al. (2013) and as further described herein.Processes for producing high cut-off membranes have been described, forexample, in the aforementioned references. As disclosed already in WO2004/056460 A1, a key element for their generation is an increase in thetemperature of the spinning process, i.e. the temperature of thespinneret, the spinning shaft temperature and temperature of thecoagulation bath, relative to the spinning conditions for producing ahigh-flux membrane with about the same composition of polymers. Inaddition, for the production of the latest high cut-off membranes suchas the Theralite® membrane, the ratio of water and solvent (H₂O/solvent)in the polymer solution is also slightly changed to lower values whilethe polymer content in said solution can otherwise be similar to or thesame as used for producing high-flux membranes such as, for example, theRevaclear® membrane.

The MWCO and MWRO values used for describing the prior art membranes andthe membranes according to the invention have been measured before bloodor plasma contact, because the sieving properties of synthetic membranesmay change after such contact. This fact can be attributed to theadhesion of proteins to the membrane surface, and is therefore relatedto the membrane material and the medium characteristics. When proteinsadhere to the membrane surface, a protein layer is created on top of themembrane. This secondary layer acts also as a barrier for the transportof substances to the membrane, and the phenomenon is commonly referredto as fouling. The general classification and typical performance ofblood purification membranes according to said reference is summarizedin Table I.

TABLE I General classification and typical performance of hemodialysismembranes Water permea- bility^(a) Sieveing Albu- ml/ Coefficient^(b)FLC min Dialyzer (m²hmm β2-Micro- Clearance^(c) Loss type Hg) globulinAlbumin Kappa Lambda (g)^(d) Low-  10-20   — <0.01 — — 0 flux High-200-400  0.7-0.8 <0.01 <10 <2 <0.5 flux Protein  50-500  0.9-1.00.02-0.03 — — 2-6 leaking High 862-1436 1.0  0.1-0.2  14-38 12-3322-28(*) cut- off ^(a)with 0.9 wt.-% sodium chloride at 37 ± 1° C. andQ_(B) 100-500 ml/min ^(b)according to EN1283 with Q_(B) max and UF 20%^(c)Serum Free Light Chains, Clearance in vitro, Q_(B) 250 ml/min andQ_(D) 500 ml/min, UF 0 ml/min, Bovine Plasma, 60 g/l, 37° C., PlasmaLevel: human κ 500 mg/1, human λ 250 mg/l. All clearances in ml/min,measured for membrane areas between 1.1 and 2.1 m² ^(d)measured inconventional hemodialysis, after a 4-h session, with Q_(B), 250 ml/minand Q_(D) 500 ml/min, for membrane areas between 1.1 and 2.1 m².

As already mentioned, sieving curves give relevant information in twodimensions: the shape of the curve describes the pore size distribution,while its position on the molecular weight axis indicates the size ofthe pores. The molecular weight cut-off (MWCO) limits the analysis ofthe sieving curve to only one dimension, namely to the size of the poreswhere the sieving coefficient is 0.1. To enhance membranecharacterization, the molecular weight retention onset (MWRO) is usedherein for characterizing the membranes according to the invention. Byusing both MWRO and MWCO it becomes evident how the membranes of theinvention distinguish themselves from prior art membranes, for typicalrepresentatives of which MWCO and MWRO have been determined under thesame conditions as for the membranes of the invention.

The MWRO is defined as the molecular weight at which the sievingcoefficient is 0.9 (see FIG. 4 of Boschetti-de-Fierro et al (2013)). Itis otherwise analogous to the MWCO but describes when the sievingcoefficient starts to fall. Defining two points on the sieving curvesallows a better, more concise characterization of the sigmoid curve,giving an indication of the pore sizes and also of the pore sizedistribution and thus of the most relevant physical parameters whichdetermine a membrane. The expression “molecular weight retention onset”,“MWRO” or “nominal molecular weight retention onset” as interchangeablyused herein therefore refers to the molecular mass of a solute where themembranes have a rejection of 10%, or, in other words, allow passage of90% of the solute, corresponding to a sieving coefficient of 0.9. Thedextran data from molecular weight fractions is also directly related tothe size of the molecules and is an indirect measure of the pore sizesin the membranes. Thus, the MWRO is also directly related to a physicalproperty of the membrane. One can interpret this value as some referenceof where the pore size distribution starts, while the MWCO indicateswhere it ends.

The use of dextran sieving curves together with the respective MWCO andMWRO values based thereon allows differentiating the existing dialyzertypes low-flux, high-flux, protein leaking, or high cut-off (see FIG. 5of Boschetti-de-Fierro et al. (2013)) and the new and improved membraneswhich is described herein. Compared, for example, to the high-fluxdialyzers, which are the standard for current dialysis treatment, thelow-flux dialyzers are depicted in a group with low MWRO and MWCO (FIG.2 ). The other two known families—protein leaking and high cut-offdialyzers—have different characteristics. While the protein leakingdialyzers are mainly characterized by a high MWCO and a low MWRO, thehigh cut-off family can be strongly differentiated due to the high invitro values for both MWRO and MWCO (Table II).

TABLE II General classification of current hemodialysis membranes basedon dextran sieving Structural Characteristics Dialyzer Pore radius typeMWRO [kDa] MWCO [kDa] [nm] Low-flux 2-4 10-20 2-3 High-flux  5-10 25-653.5-5.5 Protein 2-4 60-70 5-6 leaking High cut-off 15-20 170-320  8-12

It is obvious from FIG. 5 of Boschetti et al. (2013) that there exists agap between the currently known high cut-off and high-flux membranes,which so far could not be addressed by currently available membranes anddialyzers containing them.

Dialyzers comprising improved high-flux membranes which would be locatedin this gap are highly desirable, as they would form the nexus betweenan increasingly important removal of larger uremic solutes as realizedin present high cut-off membranes, and a sufficient retention of albuminand other essential proteins which currently puts a limit to an evenbroader usability of the beneficial characteristics of high cut-offmembranes, for example in chronic applications. Such hemodialyzers arealso desirable as they would be able to achieve performances of priorart dialyzers used in hemodiafiltration mode, thereby avoiding thedrawbacks which are connected to hemodiafiltration. However, to date, nosuch membranes or hemodialyzers have been described or prepared, eventhough continuous attempts have been made to produce such membranes(see, for example, EP 2 253 367 A1). So far, no available membrane wasable to, fulfil the above described expectations as regards MWRO andMWCO. Membranes which are coming close to said gap (EP 2 253 367 A1)could be prepared only by means of processes which are not feasible forindustrial production.

SUMMARY

It was the object of the present invention to develop an improvedhemodialysis filter which is able to combine an efficient removal ofsmall uremic molecules from blood with an enhanced removal of middle andlarge uremic solutes and an improved retention of albumin in largerproteins, which currently can be achieved, to a certain extent, only byhemodiafiltration but not by hemodialysis. In the present invention,improved hemodialyzers are disclosed which are characterized, on the onehand, by a new hollow fiber membrane having a molecular retention onset(MWRO) of between 9.0 kDa and 14.0 kDa and a molecular weight cut-off(MWCO) of between 55 kDa and 130 kDa as determined by dextran sievingcurves before the membrane has had contact with blood or a bloodproduct. On the other hand, the hemodialyzers of the invention arecharacterized by an improved overall design, comprising the singlehollow fibers, which are characterized by inner diameters of preferablybelow 200 μm and a wall thickness of preferably below 40 μm. The fibersin the bundle may be crimped or the fiber bundle may consist of 80% to95% crimped fibers and of 5% to 15% non-crimped fibers, relative to thetotal number of fibers in the bundle. The packing density of thehemodialyzers is in the range of from 50% to 65%. As a result of theoverall design of the devices, the hemodialyzers of the inventionsignificantly improve the removable range of uremic solutes whilesufficiently retaining albumin for safe use in chronic applications withpatients suffering from renal failure. In other words, the selectivityof the hemodialyzer is significantly improved compared to dialyzers ofthe prior art, which becomes evident from the combined MWRO and MWCOvalues for the membranes according to the invention. The membranes inthe context of the present invention are polysulfone-based,polyethersulfone-based or poly(aryl) ethersulfone-based syntheticmembranes, comprising, in addition, a hydrophilic component such as, forexample, PVP and optionally low amounts of further polymers, such as,for example, polyamide or polyurethane, and they are preferably producedwithout treating them with a salt solution before drying such asdisclosed in EP 2 243 367 A1. The present invention is also directed tomethods of using the filter devices in blood purification applications,in particular in hemodialysis methods used to treat advanced andpermanent kidney failure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a general, schematic representation of small, middle and largemolecular solutes which are removed by various blood purificationmembranes and operation modes in comparison. HD represents hemodialysis.HDF represents hemodiafiltration. The largest molecules will be removedby high cut-off membranes (hemodialysis mode). High-flux membranes, inhemodialysis mode, are able to remove small molecules and certain middlemolecules in hemodialysis, whereas the same membranes will remove largermiddle molecules in hemodiafiltration mode. The membranes according tothe invention are able to remove also large molecules such as IL-6 andλ-FLC, comparable or superior to HDF, but in hemodialysis mode.Essential proteins like, for example, albumin are essentially retained.

FIG. 2 shows the results of dextran sieving measurements wherein theMWRO (molecular weight retention onset) is plotted against the MWCO(molecular weight cut-off). Each measuring point represents threedextran sieving measurements of a given membrane. Dextran sievingmeasurements were performed according to Example 3. The respective MWCOand MWRO values were measured and the average value for a given membranewas entered into the graph shown. The membranes marked with a triangle(▴) and contained in two squares of varying sizes are membranesaccording to the invention and have been prepared in accordance withExample 1. The data points outside the square(s) are prior art membraneswhich are either low-flux membranes (●; a-c), high-flux membranes (◯;1-13), high cut-off membranes (Δ; α, β, γ, ϕ) or so-calledprotein-leaking membranes (▾). It is evident from the graph that themembranes according to the invention (▴; A-G) form a new type ofmembranes which in the representation of MWRO against MWCO is locatedbetween the high-flux and high cut-off membranes of the prior art. Therespective membranes, the processes for preparing them and/or theiridentity are provided for in further detail in Example 1.

FIG. 3 is a schematic representation of the experimental setup for thefiltration experiments according to Example 3, showing: (1) pool withdextran solution, (2) feed pump, (3) manometer, feed side Pin, (4)manometer, retentate side Pout, (5) manometer, filtrate side PUF, (6)filtrate pump (with less than 10 ml/min), (7) heating/stirring plate.

FIG. 4 exemplarily shows clearance curves for urea (FIG. 4A) and formyoglobin (FIG. 4B). See also Table V. Clearances are shown at UF=0ml/min for a hemodialyzer according to the present invention based onMembrane A (1.7 m²,

), a high flux dialyzer based on Membrane 6 (1.8 m²,

) and a hemodialyzer based on Membrane β (2.1 m²,

).

FIG. 5 exemplarily shows clearance curves for phosphate (FIG. 5A) andfor cytochrome C (FIG. 5B). See also Table VI. Clearances are shown atUF=0 ml/min for a hemodialyzer according to the present invention basedon Membrane A (1.7 m²,

), FX_(CorDiax)80 (1.8 m²,

) and FX_(CorDiax)100 (2.2 m²,

) in hemodialysis mode.

FIG. 6 exemplarily shows clearance curves for phosphate (FIG. 6A) andfor cytochrome C (FIG. 6B). See also Table VII. Clearances are shown atUF=0 ml/min for a hemodialyzer according to the present invention basedon Membrane A (1.7 m²,

), and f or FX_(CorDiax)800 (2.0 m²,

) and FX_(CorDiax)1000 (2.3 m²,

) at UF=75 ml/min and UF=100 ml/min, respectively.

FIG. 7 exemplarily shows clearance curves for phosphate (FIG. 7A) andfor cytochrome C (FIG. 7B). See also Table VIII. Clearances are shown atUF=0 ml/min for a hemodialyzer according to the present invention basedon Membrane A (1.7 m²,

), and hemodiafilters (Nephros OLpūr™ MD 220 (2.2 m²,

) and Nephros OLpūr™ MD 190 (1.9 m²,

), with Q_(S)=200 ml/min, corresponding to an UF of 200 ml/min.

FIG. 8A to F exemplarily show scanning electron micrographs of MembraneA according to the invention. Magnifications used are indicated in eachFigure. FIG. 8A shows a profile of the hollow fiber membrane, whereasFIG. 8B a close-up cross-section through the membrane, where the overallstructure of the membrane is visible. FIGS. 8C and 8D represent furthermagnifications of the membrane wall, wherein the inner selective layeris visible. FIG. 8E shows the inner selective layer of the membrane,FIG. 8F shows the outer surface of the hollow fiber membrane.

FIG. 9A to F exemplarily show scanning electron micrographs of MembraneF according to the invention. Magnifications used are indicated in eachFigure. FIG. 9A shows a profile of the hollow fiber membrane, whereasFIG. 9B a close-up cross-section through the membrane, where the overallstructure of the membrane is visible. FIGS. 9C and 9D represent furthermagnifications of the membrane wall, wherein the inner selective layeris visible. FIG. 9E shows the inner selective layer of the membrane,FIG. 9F shows the outer surface of the hollow fiber membrane.

DETAILED DESCRIPTION

Middle molecules, consisting mostly of peptides and small proteins withmolecular weight the range of 500-60,000 Da, accumulate in renal failureand contribute to the uremic toxic state. These solutes are not wellcleared by low-flux dialysis. High-flux dialysis will clear middlemolecules, partly by internal filtration. Many observational studiesover the last years have indeed supported the hypothesis that highermolecular weight toxins (FIG. 1 ) are responsible for a number ofdialysis co-morbidities, including, for example, chronic inflammationand related cardiovascular diseases, immune dysfunctions, anaemia etc.,influencing also the mortality risk of chronic hemodialysis patients. Itis possible to enhance the convective component of high-flux dialysis byhaemodiafiltration (HDF). However, in case of postdilution HDF,increasing blood flow above the common routine values may createproblems of vascular access adequacy in many routine patients and istherefore not accessible to all patients in need. Predilution HDF allowsfor higher infusion and ultrafiltration rates. However, this advantagein terms of convective clearances is thwarted by dilution of the soluteconcentration available for diffusion and convection, resulting in thereduction of cumulative transfer. Therefore, there is an increasinginterest in accomplishing filter devices which in hemodialysis modeallow an enhanced transport of middle and even large molecules and areliable and efficient removal of small solutes such as urea, comparableor superior to high-flux membranes when used in HDF mode, while at thesame time efficiently retaining albumin and larger essential proteinssuch as coagulation factors, growth factors and hormones. In short, suchdesired hemodialyzers are able to provide the best possible clearancefor low and highmolecular weight uremic toxins by hemodialysis, which isat least comparable and preferably superior to the clearance of saidtoxins in haemodiafiltration treatments. In other words, thehemodialyzers of the invention at an average blood flow of between 200and 600 ml/min 350-450 ml/min, a dialysate flow of between 300-1000ml/min and an ultrafiltration rate of 0-30 ml/min are designed toprovide for clearance rates determined in vitro according toIS08637:2014(E) for a given substance generally used to define theclearance performance of a dialyzer, such as, for example, cytochrome Cor myoglobin, which are about equivalent or higher than those achievedwith dialyzers comprising high flux membranes at the same Q_(B) rate andan ultrafiltration rate of above 50 ml/min. The expression “equivalent”as used herein refers to clearance values which deviate from each otherby not more than ±10%, preferably by not more than ±5%. According to oneembodiment of the invention, the ultrafiltration rate used with ahemodialyzer of the invention is between 0 and 20 ml/min. According toanother embodiment of the invention, the ultrafiltration rate used witha hemodialyzer of the invention is between 0 and 15 ml/min. According toyet another embodiment of the invention, the ultrafiltration rate is 0ml/min. The blood flow range used with a hemodialyzer of the inventionaccording to another embodiment of the invention will be in the range ofbetween 350-450 ml/min, and the dialysate flow will be in the range offrom between 500 and 800 ml/min.

If used, for example, at a blood flow of between 200-500 ml/min, adialysate flow of between 500-800 ml/min and an ultrafiltration rate ofbetween 0 and 30 ml/min the albumin loss per treatment (240 min±20%)with a hemodialysis filter according to the invention is limited to amaximum of 7 g. According to one aspect of the present invention, thealbumin loss under the same conditions is limited to 4 g, see alsoExample 5.

In the context of the present invention, the expressions“hemodialyzer(s)”, “hemodialysis device”, “hemodialysis filter”, “filterfor hemodialysis” or “filter device for hemodialysis” are usedsynonymously and refer to the devices according to the invention asdescribed herein. The expression “hemodiafilter(s)” as used hereinrefers to filter devices which can be used or are preferably used inblood treatments performed in hemodiafiltration methods for bloodpurification. The expressions “dialyzer”, “dialysis filter”, “filter” or“filter device”, if not indicated otherwise, generally refer to deviceswhich can be used for blood purification.

The expression “hemodialysis” as used herein refers to a primarilydiffusive-type blood purification method wherein the differences inconcentration drive the removal of uremic toxins and their passagethrough the dialyzer membrane which separates the blood from thedialysate. The expression “hemodiafiltration” as used herein refers to ablood purification method that combines diffusion and convection,wherein convection is achieved by applying a positive pressure gradientacross the dialyzer membrane.

The hemodialyzers now accomplished are further characterized byclearance rates, determined according to ISO8637:2014(E), that inhemodialysis mode achieve values which can be achieved with prior artdialyzers only in hemodiafiltration mode, i.e. by applying a positivepressure gradient across the dialyzer membrane.

Dialyzers generally comprise a cylindrical housing or casing. Locatedwithin the interior of the casing is a fiber bundle. Typically the fiberbundle is comprised of a number of hollow fiber membranes that areoriented parallel to each other. The fiber bundle is encapsulated ateach end of the dialyzer in a potting material to prevent blood flowaround the fibers and to provide for a first flow space surrounding themembranes on the outside and a second flow space formed by the fibercavities and the flow space above and below said potting material whichis in flow communication with said fiber cavities. The dialyzersgenerally further consist of end caps capping the mouths of the tubularsection of the device which also contains the fiber bundle. The dialyzerbody also includes a dialysate inlet and a dialysate outlet. Accordingto one embodiment of the invention, the dialysate inlet and dialysateoutlet define fluid flow channels that are in a radial direction, i.e.,perpendicular to the fluid flow path of the blood. The dialysate inletand dialysate outlet are designed to allow dialysate to flow into aninterior of the dialyzer, bathing the exterior surfaces of the fibersand the fiber bundle, and then to leave the dialyzer through the outlet.The membranes are designed to allow blood to flow therethrough in onedirection with dialysate flowing on the outside of the membranes inopposite direction. Waste products are removed from the blood throughthe membranes into the dialysate. Accordingly, dialyzers typicallyinclude a blood inlet and a blood outlet, the blood inlet being designedto cause blood to enter the fiber membranes and flow therethrough.Dialysate is designed to flow through an inlet of the dialyzer and outof the dialyzer through an outlet, thereby passing the outside orexterior walls of the hollow fiber membranes.

A variety of dialyzer designs can be utilized for accomplishing thepresent invention. According to one embodiment the hemodialyzers of theinvention have designs such as those set forth in WO 2013/190022 A1.However, other designs can also be utilized without compromising thegist of the present invention.

The packing density of the hollow fiber membranes in the hemodialyzersof the present invention is from 50% to 65%, i.e., the sum of thecross-sectional area of all hollow fiber membranes present in thedialyzer amounts to 50 to 65% of the cross-sectional area of the part ofthe dialyzer housing comprising the bundle of semi-permeable hollowfiber membranes. According to one embodiment of the present invention,the packing density of the hollow fiber membranes in the hemodialyzersof the present invention is from 53% to 60%. If n hollow fiber membranesare present in the bundle of semi-permeable hollow fiber membranes,D_(F) is the outer diameter of a single hollow fiber membrane, and D_(H)is the inner diameter of the part of the dialyzer housing comprising thebundle, the packing density can be calculated according ton*(D_(F)/D_(H))². A typical fiber bundle with fibers according to theinvention, wherein the fibers have a wall thickness of 35 μm and aninner diameter of 180 μm, and which is located within a housing havingan inner diameter of, for example, 38 mm, wherein the fibers have aneffective fiber length of 236 mm and wherein packing densities ofbetween 53% to 60% are realized, will contain about 12 500 to 13 500fibers, providing for an effective surface area of about 1.7 m². Ingeneral, the effective surface area can be chosen to be in the rangesknown in the art. Useful surface areas will lie, for example, in therange of from 1.1 m² to 2.5 m². It will be readily understood by aperson skilled in the art that housing dimensions (inner diameter,effective length) will have to be adapted for achieving lower or highermembrane surface areas of a device, if fiber dimensions and packingdensities remain the same.

According to one aspect of the present invention, a bundle of hollowfiber membranes is present in the housing or casing, wherein the bundlecomprises crimped fibers. The bundle may contain only crimped fibers,such as described, for example, in EP 1 257 333 A1. According to anotheraspect of the invention, the fiber bundle may consist of 80% to 95%crimped fibers and from 5% to 15% non-crimped fibers, relative to thetotal number of fibers in the bundle, for instance, from 86 to 94%crimped fibers and from 6 to 14% non-crimped fibers. In one embodiment,the proportion of crimped fibers is from 86 to 92%. The fibers have asinusoidal texture with a wavelength in the range of from 6 to 9 mm, forinstance, 7 to 8 mm; and an amplitude in the range of from 0.1 to 0.5mm; for instance 0.2 to 0.4 mm. Incorporation of 5 to 15% non-crimpedfibers into a bundle of crimped semi-permeable hollow fiber membranesmay enhance the performance of the hemodialyzer of the invention. Forinstance, with an unchanged packing density of the fibers within thedialyzer, the clearance of molecules like urea, vitamin B12, orcytochrome C from a fluid passing through the fiber lumen is increased.It is believed that this effect is due to improved flow of dialysisliquid in the second flow space of the dialyzer and around theindividual fibers in the bundle. Another advantage of the incorporationof 5 to 15% non-crimped fibers into a bundle of crimped semi-permeablehollow fiber membranes is that packing densities can be achieved whichare higher than those in bundles exclusively containing crimped fibers.As a consequence, a larger effective membrane area can be fitted into agiven volume of the internal chamber of the hemodialyzer. Also, a giveneffective membrane area can be fitted into a smaller volume, whichallows for further miniaturization of the hemodialyzer. Anotheralternative offered by the incorporation of 5 to 15% non-crimped fibersinto a bundle of crimped semi-permeable hollow fiber membranes is thatthe crimp amplitude of the crimped fibers within the bundle can beincreased at constant packing density and constant volume of theinternal chamber, while the resilience of the bundle is kept at a valuewhich does not require excessive force for the transfer of the bundleinto the housing. This helps to avoid increased scrap rates in dialyzerproduction. When less than about 5% of non-crimped fibers are present inthe bundle of semi-permeable hollow fiber membranes, no substantialdifference in dialyzer performance is observed in comparison to adialyzer comprising crimped fibers only. On the other hand, when morethan about 15% of non-crimped fibers are present in the bundle, adecrease of dialyzer performance is noted. A potential explanation forthis effect could be that, with increasing proportion of non-crimpedfibers within the bundle, non-crimped fibers may contact and adhere toeach other, thus reducing membrane surface area available for masstransfer through the hollow fiber walls.

The hollow fiber membranes used for accomplishing the hemodialyzer ofthe present invention, due to their specific design, are characterizedby an increased ability to remove larger molecules while at the sametime effectively retaining albumin. The membranes are characterized by amolecular retention onset (MWRO) of between 9.0 kDa and 14.0 kDa and amolecular weight cut-off (MWCO) of between 55 kDa and 130 kDa asdetermined by dextran sieving (FIG. 2 ). Thus, according to one aspectof the present invention, the membranes are characterized by a MWRO ofbetween 9000 and 14000 Daltons as determined by dextran sievingmeasurements, which indicates that the membranes according to theinvention have the ability to let pass 90% of molecules having amolecular weight of from 9.0 to 14.5 kDa. Notably, said MWRO is achievedin hemodialysis (HD) mode. The molecules of said molecular weight rangebelong to the group of molecules generally referred to as middlemolecules which otherwise can only efficiently be removed by certainhigh cut-off membranes at the cost of some albumin loss or by certainhigh-flux membranes which are used in HDF mode. According to anotheraspect of the invention, the membranes are further characterized by aMWCO of between 55 kDa and 130 kDa Daltons as determined by dextransieving, which indicates that the membranes are able to effectivelyretain larger blood components such as albumin (67 kDa) and moleculeslarger than said albumin. In contrast, the average MWRO range ofhigh-flux membranes lies in the range of from about 4 kDa to 10 kDa asdetermined by dextran sieving, combined with a MWCO of from about 19 kDato about 65 kDa as determined by dextran sieving. High cut-off membranesare characterized by a significantly higher MWCO, as determined bydextran sieving, of from about 150-320 kDa, and a MWRO, as determined bydextran sieving of between 15-20 kDa.

According to another aspect of the present invention, the membranes ofthe invention have a MWRO, as determined by dextran sieving, in therange of from 9.0 kDa to 12.5 kDa and a MWCO, as determined by dextransieving, in the range of from 55 kDa to 110 kDa. According to anotheraspect of the present invention, the membranes being part of theinvention have a MWRO, as determined by dextran sieving, in the range offrom 9.0 kDa to 12.5 kDa and a MWCO, as determined by dextran sieving,in the range of from 68 kDa to 110 kDa. According to yet another aspectof the present invention, the membranes have a MWRO, as determined bydextran sieving, in the range of from 10 kDa to 12.5 kDa and a MWCO, asdetermined by dextran sieving, in the range of from 68 kDa to 90 kDa.According to yet another aspect of the present invention, membranes havea MWRO, as determined by dextran sieving, of more than 10.0 kDa and lessthan 12.5 kDa and a MWCO, as determined by dextran sieving, of more than65.0 kDa and less than 90.0 kDa.

As mentioned before, the membranes according to the invention are ableto selectively control albumin loss and loss of other essential highermolecular weight blood components. In general, a hemodialyzer accordingto the invention with an effective membrane area of from 1.7 m² to 1.8m² limits the protein loss in vitro (Q_(B)=300 ml/min, TMP=300 mmHg,bovine plasma with total protein concentration 60±5 g/l) after 25minutes to a maximum of from 1.0 to 2.0 g/l. According to one embodimentof the invention the dialyzers with an effective membrane area of from1.7 m² to 1.8 m² have a protein loss in vitro (Q_(B)=300 ml/mm, TMP=300mmHg, bovine plasma with total protein concentration 60±5 g/l) after 25minutes of at most 1.2 or, according to another aspect of the invention,of at most 1.4 g/l. According to another aspect of the presentinvention, the hemodialyzer according to the invention with an effectivemembrane area of between 1.1 and 2.5 m² limits albumin loss pertreatment (240 min±20%) at a blood flow of between 200-600 ml/min, adialysate flow of between 300-1000 ml/min and an ultrafiltration rate of0 to 30 ml/min, to a maximum of 7 g (Example 5). According to a furtheraspect of the invention the said effective surface area is between 1.4and 2.2 m² and blow flow is between 200 and 500 ml/min, dialysate flowbetween 500 and 800 ml/min, and ultrafiltration rate between 0 and 20ml/min. According to one aspect of the present invention, albumin lossunder the aforementioned conditions is below 4 g. According to yetanother aspect of the present invention, the above maximum values foralbumin loss are reached at ultrafiltration rates of between 0 ml/minand 10 ml/min.

Membrane passage of a solute such as a protein which needs to be removedfrom blood or needs to be retained, as the case may be, is described bymeans of the sieving coefficient S. The sieving coefficient S iscalculated according to S=(2C_(F))/(C_(Bin)+C_(Bout)), where C_(F) isthe concentration of the solute in the filtrate and C_(Bin) is theconcentration of a solute at the blood inlet side of the device undertest, and C_(Bout) is the concentration of a solute at the blood outletside of the device under test. A sieving coefficient of S=1 indicatesunrestricted transport while there is no transport at all at S=0. For agiven membrane each solute has its specific sieving coefficient. Themembranes of the hemodialyzer according to the invention have an averagesieving coefficient for albumin, measured in bovine plasma according toDIN EN ISO8637:2014 at Q_(B)=400 ml/min and UF=25 ml/min of between 0.01and 0.2. According to another aspect of the invention, the membranesaccording to the invention have an average sieving coefficient foralbumin, measured in bovine plasma according to DIN EN ISO8637:2014 atQ_(B)=400 ml/min and UF=25 ml/min of between 0.02 and 0.1. According toyet another aspect of the invention, the membranes according to theinvention have an average sieving coefficient for albumin, measured inbovine plasma according to DIN EN ISO8637:2014 at Q_(B)=400 ml/min andUF=25 ml/min of between 0.02 and 0.08. According to another aspect ofthe invention, the membranes according to the invention have an averagesieving coefficient for albumin, measured in bovine plasma according toEN1283 (Q_(B)max, UF=20%) at Q_(B)=600 ml/min and UF=120 ml/min ofbetween 0.01 and 0.1. According to yet another aspect of the invention,the membranes according to the invention have an average sievingcoefficient for albumin, measured in bovine plasma according to EN1283(Q_(B)max, UF=20%) at Q_(B)=600 ml/min and UF=120 ml/min of between 0.01and 0.06.

The semipermeable hemodialysis membrane of the hemodialyzer according tothe invention comprises at least one hydrophilic polymer and at leastone hydrophobic polymer. In one embodiment, said at least onehydrophilic polymer and at least one hydrophobic polymer are present ascoexisting domains on the surface of the dialysis membrane. Thehydrophobic polymer may be chosen from the group consisting ofpoly(aryl)ethersulfone (PAES), polysulfone (PSU) and polyethersulfone(PES) or combinations thereof. In a specific embodiment of theinvention, the hydrophobic polymer is chosen from the group consistingof poly(aryl)ethersulfone (PAES) and polysulfone (PSU). The hydrophilicpolymer will be chosen from the group consisting of polyvinylpyrrolidone(PVP), polyethyleneglycol (PEG), polyvinylalcohol (PVA), and a copolymerof polypropyleneoxide and polyethyleneoxide (PPO-PEO). In anotherembodiment of the invention, the hydrophilic polymer may be chosen fromthe group consisting of polyvinylpyrrolidone (PVP), polyethyleneglycol(PEG) and polyvinylalcohol (PVA). In one specific embodiment of theinvention, the hydrophilic polymer is polyvinylpyrrolidone (PVP).

The membrane used for accomplishing the hemodialyzer of the invention isa hollow fiber having an asymmetric foam- or sponge-like and/or afinger-like structure with a separation layer present in the innermostlayer of the hollow fiber. According to one embodiment of the invention,the hollow fiber membrane used has an asymmetric “sponge-like” or foamstructure (FIG. 9 ). According to another embodiment of the invention,the membrane of the invention has an asymmetric structure, wherein theseparation layer has a thickness of less than about 0.5 μm. In oneembodiment, the separation layer contains pore channels having anaverage pore size (radius) of between about 5.0 and 7.0 nm as determinedfrom the MWCO based on dextran sieving coefficients according toBoschetti-de-Fierro et al. (2013) and Granath et al. (1967). The averagepore size (radius) before blood contact is generally above 5.0 nm andbelow 7.0 nm for this type of membrane (FIG. 8 ) and specifically above5.0 nm and below 6.7 nm. The next layer in the hollow fiber membrane isthe second layer, having the form of a sponge structure and serving as asupport for said first layer. In a preferred embodiment, the secondlayer has a thickness of about 1 to 15 μm. The third layer has the formof a finger structure. Like a framework, it provides mechanicalstability on the one hand; on the other hand a very low resistance tothe transport of molecules through the membrane, due to the high volumeof voids, is achieved. The third layer has a thickness of 20 to 30 μm.In another embodiment of the invention, the membranes can be describedto include a fourth layer, which is the outer surface of the hollowfiber membrane. This fourth layer has a thickness of about 1 to 10 μm.As can easily be understood, a combination of the above ranges willalways add up to a wall thickness within the aforementioned ranges forwall thicknesses of the hollow fiber membranes in accordance with thepresent invention.

The manufacturing of a membrane as it is used for accomplishing thepresent invention follows a phase inversion process, wherein a polymeror a mixture of polymers is dissolved in a solvent or solvent mixture toform a polymer solution. The solution is degassed and filtered beforespinning. The temperature of the polymer solution is adjusted duringpassage of the spinning nozzle (or slit nozzle) whose temperature can beregulated and is closely monitored. The polymer solution is extrudedthrough said spinning nozzle (for hollow fibers) or a slit nozzle (for aflat film) and after passage through the so-called spinning shaft entersinto said precipitation bath containing a non-solvent for the polymerand optionally also a solvent in a concentration of up to 20 wt.-%. Toprepare a hollow fiber membrane, the polymer solution preferably isextruded through an outer ring slit of a nozzle having two concentricopenings. Simultaneously, a center fluid is extruded through an inneropening of the spinning nozzle. At the outlet of the spinning nozzle,the center fluid comes into contact with the polymer solution and atthis time the precipitation is initialized. The precipitation process isan exchange of the solvent from the polymer solution with thenon-solvent of the center fluid. By means of this exchange the polymersolution inverses its phase from the fluid into a solid phase. In thesolid phase the pore structure and the pore size distribution isgenerated by the kinetics of the solvent/non-solvent exchange. Theprocess works at a certain temperature which influences the viscosity ofthe polymer solution. For preparing membranes according to theinvention, the temperature of the spinning nozzle and, consequently, ofthe polymer solution and the center fluid as well as the temperature ofthe spinning shaft should be carefully controlled. In principle,membranes of the invention can be prepared at a comparatively broadtemperature range. Temperature may thus be in the range of between 30and 70° C. However, for producing a membrane of the invention, theultimate temperature should be chosen by taking account of the polymercomposition and the temperature which would otherwise be used forproducing a standard high-flux membrane with about the same polymercomposition and which can be used as a starting point for the productionof a membrane according to the invention. In general, there are twoparameters which can be effectively influenced in order to arrive atmembranes of the present invention. First, the temperature at thespinning nozzle should be slightly raised by about 0.5° C. to 4° C.relative to the temperatures used for producing a high-flux typemembrane having about the same polymer composition, resulting in acorresponding increase of the temperature of the polymer solution.Second, the water content in the center solution should be slightlyreduced in a range of from 0.5 wt.-% to 4 wt.-%, preferably from 0.5wt.-% to 3 wt.-%. It should be obvious that the polymer composition forpreparing a membrane according to the invention does not have to becompletely identical to a typical polymer composition for preparing ahigh-flux membrane, such as, for example, Membrane 6 (Example 1).Accordingly, expressions such as “about the same polymer composition” asused in the present context refers to polymer compositions having thesame basic composition, for example, a combination of PS, PES or PAES onthe one hand and PVP on the other hand, in concentrations typically usedfor the production of high-flux type membranes and/or membranesaccording to the present invention.

As mentioned before, the temperature influences the viscosity of thespinning solution, thereby determining the kinetics of the pore-formingprocess through the exchange of solvent with non-solvent. The viscosityof a spinning solution for preparing membranes according to theinvention generally should be in the range of from 3000 to 7400 mPas at22° C. According to one embodiment of the invention, the viscosity is inthe range of from 4900 to 7400 mPas (22° C.). According to yet anotherembodiment of the invention the viscosity will be in the range of from4400 to 6900 mPas (22° C.). For arriving at foam- or sponge-likestructures the viscosity can, for example, be increased to values of upto 15000 mPas, even though such structures can also be obtained withlower values in the above-stated ranges.

Another aspect of preparing a membrane comprised by the hemodialyzeraccording to the invention concerns the temperature of the center fluid.The center fluid generally comprises 45 to 60 wt.-% of a precipitationmedium, chosen from water, glycerol and other alcohols, and 40 to 55wt.-% of solvent. In other words, the center fluid does not comprise anyhydrophilic polymer. The temperature of the center fluid is in principlethe same as the temperature chosen for the spinning nozzle as thetemperature of the center fluid will be determined when it passesthrough said nozzle. According to one embodiment of the invention, thecenter fluid is composed of water and NMP, wherein the water is presentin a concentration of from 50 to 58 wt.-%.

According to a further embodiment of the invention, the polymer solutioncoming out through the outer slit openings is, on the outside of theprecipitating fiber, exposed to a humid steam/air mixture. Preferably,the humid steam/air mixture in the spinning shaft has a temperature ofbetween 50° C. to 60° C. According to one embodiment of the invention,the temperature in the spinning shaft is in the range of from 53° C. to58° C. The distance between the slit openings and the precipitation bathmay be varied, but generally should lie in a range of from 500 mm to1200 mm, in most cases between 900 mm and 1200 mm. According to oneembodiment of the invention the relative humidity is >99%.

According to another aspect of the present invention, following passagethrough the spinning shaft the hollow fibers enter a precipitation bathwhich generally consists of water having a temperature of from 12° C. to30° C. For preparing the membranes according to the invention, thetemperature of the precipitation bath may be slightly elevated by 1 to10° C. in comparison to the temperature which would otherwise be chosenfor preparing a high-flux or high cut-off membrane. According to oneembodiment of the invention an increase by 2° C. to 10° C. and morespecifically an increase of up to 6° C. may be recommendable to arriveat membranes of the present invention.

According to one specific embodiment of the invention, the temperatureof the precipitation bath is between 23° C. and 28° C. The membraneaccording to the present invention will then be washed in consecutivewater baths to remove waste components and can then directly besubmitted to, for example, online drying at temperatures of between 150°C. to 280° C. without any further treatment such as the below mentionedsalt bath.

In order to illustrate what has been said before, a membrane accordingto the invention can be produced as follows. For a composition based onpoly(aryl)ethersulfone, polyethersulfone or polysulfone and PVP, thetemperature of the spinning nozzle, for example, can be chosen to be ina range of from 56° C. to 59° C., and the temperature of the spinningshaft is then in the range of from 53° C. to 56° C. in order to reliablyarrive at a membrane according to the invention. Preferably, thetemperature of the spinning nozzle is in the range of from 57° C. to 59°C., more preferably in a range of from 57° C. to 58° C., and thetemperature in the spinning shaft is then in the range of from 54° C. to56° C. In each case the viscosity of the spinning solution afterpreparation should be in the range of from 3000 to 7400 mPas at 22° C.Such composition, may, for example, comprise 14 wt.-% ofpoly(aryl)ethersulfone, polyethersulfone or polysulfone, 7 wt.-% of PVP,77 wt.-% of a solvent, such as NMP, and 2 wt.-% of water. At the sametime, the center solution should comprise, for example, 54.0 to 55 wt.-%water and 46.0 to 45.0 wt.-% solvent, e.g. NMP, respectively. Forexample, the center solution may contain 54.5% water and 45.5 solvent,such as NMP.

The spinning velocity often may influence the properties of theresulting membranes. In the present case, the velocity may be chosen tobe in a relatively broad range from about 10 to 60 m/min withoutdeparting from the invention, even though higher spinning velocitieswhich still provide for a stable production process will be desirablefor economic reasons. According to one embodiment of the invention, thespinning velocity for arriving at membranes as used for accomplishinghemodialyzers according to the invention will therefore be in the rangeof from 30 to 50 m/min. According to another embodiment of theinvention, the spinning velocity for arriving at membranes as used foraccomplishing hemodialyzers according to the invention will be in therange of from 40 to 55 m/min.

According to one embodiment of the invention, the polymer solution usedfor preparing the membrane preferably comprises 10 to 20 wt.-% of thehydrophobic polymer, 2 to 11 wt.-% of the hydrophilic polymer, as wellas water and a solvent, such as, for example, NMP. Optionally, lowamounts of a second hydrophobic polymer can be added to the polymersolution. The spinning solution for preparing a membrane according tothe present invention preferably comprises between 12 and 15 weight-% ofpolyethersulfone or polysulfone as hydrophobic polymer and 5 to 10weight-% of PVP, wherein said PVP may consist of a low and a highmolecular PVP component. The total PVP contained in the spinningsolution thus may consist of between 22 and 34 weight-% and preferablyof between 25 and 30 weight-% of a high molecular weight component andof between 66 and 78 weight-%, preferably of between 70 and 75 weight-%of a low molecular weight component. Examples for high and low molecularweight PVP are, for example, PVP K85/K90 and PVP K30, respectively. Thesolvent may be chosen from the group comprising N-methylpyrrolidone(NMP), dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO) dimethylformamide (DMF), butyrolactone and mixtures of said solvents. Accordingto one embodiment of the invention, the solvent is NMP.

As mentioned before, the type, amount and ratio of hydrophilic andhydrophobic polymers used for producing membranes according to theinvention may be similar to or the same as those which would otherwisebe used for the production of high-flux membranes which are known in theart. It may, however, be recommendable for arriving at membranesaccording to the invention to adjust the ratio of water and solvent(H₂O/solvent) in the polymer solution compared to standard high-fluxrecipes to slightly lower values, i.e. to slightly decrease the totalconcentration of water in the polymer solution by about 0.5 wt.-% to 4wt.-% and to adjust the amount of solvent accordingly by slightlyincreasing the total concentration of the respective solvent. In otherwords, for a given polymer solution, the amount of water will beslightly reduced and the amount of solvent will at the same time andrate be slightly increased compared to polymer compositions used forstandard high-flux membranes As an alternative way to arrive atmembranes for hemodialyzers according to the invention it is alsopossible to choose, as a starting point, known recipes and processes forpreparing high cut-off membranes. In this case, the polymer composition,including water and solvent, will generally remain about the same as acomposition typically used for preparing high cut-off membranes, such asshown for Membranes α and β. However, the ratio of H₂O and solvent inthe center solution should be increased as compared to the typicalcenter solution used for preparing a high cut-off membrane, such as, forexample, for Membranes α and β, i.e. the water content is slightlyincreased by about 0.5 wt.-% to 4.0 wt.-%.

The slight increase in the water content in the center solution shouldbe accompanied by an adaption of the spinning nozzle and spinning shafttemperature. An increase in water content will generally be accompaniedby appropriately adapting the temperature of the spinneret and thespinning shaft by up to 4° C., preferably by about between 0.5° C. to 3°C., relative to the respective temperatures used for producing a highcut-off type membrane. Depending on the aspired characteristics of themembranes according to the invention in terms of MWRO and MWCO values,the change in the water content of the center solution can beaccompanied, for example, by a temperature increase of up to 4° C.,preferably by 0.5° C. to 3° C., resulting in rather open-pored membranespecies which would be located in the upper right corner of the squareshown in FIG. 2 . It may also be accompanied by a very slight or nosignificant increase of the temperature or even by a decrease of thespinneret's and spinning shaft's temperature by about 0.5° C. to 2° C.,respectively, resulting in a less open-pored, more high-flux likemembrane species which would be located in the lower left corner of thesquare shown in FIG. 2 .

Accordingly, it is one aspect of the present invention, that themembranes according to the invention can be obtained by dissolving atleast one hydrophobic polymer component and at least one hydrophilicpolymer in at least one solvent to form a polymer solution having aviscosity of from 3000 to 7400 mPas at a temperature of 22° C.,extruding said polymer solution through an outer ring slit of a spinningnozzle with two concentric openings and extruding a center fluidcomprising at least one solvent and water through the inner opening ofthe nozzle, passing the polymer solution through a spinning shaft into aprecipitation bath, wherein the distance between the slit openings andthe precipitation bath is between 500 mm to 1200 mm, preferably between900 mm and 1200 mm, and wherein the relative humidity of the steam/airmixture in the spinning shaft is between 60% and 100%, washing themembrane obtained, drying said membrane and, optionally, sterilizingsaid membrane by steam treatment, wherein the content of water in thecenter solution is increased by between 0.5 wt.-% and 4 wt.-% relativeto the water content which is used for preparing a high-cut off membranehaving the same polymer composition, and wherein the temperature of thespinning nozzle and the spinning shaft is either decreased by up to 2.0°C., preferably by 0.5° C. to 2° C., relative to the temperature whichwould be used for preparing a high-cut off membrane having the samepolymer composition, or is increased by 0.5° C. to 4° C., preferably0.5° C. to 3° C., relative to the temperature which would be used forpreparing a high-cut off membrane having the same polymer composition,or remains the same.

The membrane after washing and without being immersed in any salt bathcan directly be submitted to a drying step, such as online drying, andis then preferably steam sterilized at temperatures above 121° C. for atleast 21 minutes. It is, however, also possible to use other methodsknown in the art for sterilizing the membrane and/or the filter devicecomprising same.

A membrane according to the invention which is based on, for example,poly(aryl)ethersulfone and PVP, after preparation comprises from between2.0 wt.-% to 4.0 wt.-% PVP and poly(aryl)ethersulfone adding up to 100%,respectively.

Hollow fiber membranes as used in hemodialyzers according to theinvention can be produced with different inner and outer diameters andthe wall thickness of such hollow fiber membranes may vary over acertain range. High cut-off membranes known in the art, such as, forexample, Theralite® and HCO1100®, have a comparatively large innerdiameter of the fiber of 215 μm and a wall thickness of 50 μm. Knownhigh-flux membranes such as used, for example, in the Revaclear® 400filter have inner diameters of 190 μm and a wall thickness of 35 μm, or,in the case of the FX CorDiax hemodiafilters, an inner diameter of 210μm. Membranes according to the invention are preferably prepared with awall thickness of below 55 μm, generally with a wall thickness of from30 to 49 μm. The membranes can, however, be produced with a wallthickness of below 40 μm, generally in the range of about 30 to 40 μm,such as, for example, with a wall thickness of 35 μm. The inner diameterof the hollow fiber membranes of the present invention may be in therange of from 170 μm to 200 μm, but may generally be reduced to below200 μm or even below 190 μm, for example to about 175 μm to 185 μm forfull efficiency in the context of the present invention.

The membranes used in hemodialyzers according to the invention can befurther characterized by an average sieving coefficient for β2-M,measured in bovine plasma (total protein 60±5 g/l total protein)according to EN1283 (Q_(B)max, UF=20%) with blood flow rates of between400 ml/min and 600 ml/min of between 0.7 and 1. According to anotherembodiment of the invention the sieving coefficients for β2-M under thesame conditions are between 0.8 and 1. According to yet anotherembodiment of the invention the sieving coefficients for β2-M under thesame conditions are between 0.9 and 1. According to another embodimentof the invention the sieving coefficients for β2-M measured according toDIN EN ISO8637:2014 at Q_(B)=400 ml/min and UF=25 ml/min are between 0.8and 1. According to yet another embodiment of the invention the sievingcoefficients for β2-M under the same conditions are between 0.9 and 1.

The membranes can also be characterized by an average sievingcoefficient for myoglobin, measured in bovine plasma according to EN1283(Q_(B)max, UF=20%) with blood flow rates of between 400 ml/min and 600ml/min of between 0.7 and 1. According to another embodiment of theinvention the sieving coefficients for myoglobin under the sameconditions are between 0.8 and 1, more specifically between 0.9 and 1.According to another embodiment of the invention the sievingcoefficients for myoglobin, measured according to DIN EN ISO8637:2014 atQ_(B)=400 ml/min and UF=25 ml/min are between 0.8 and 1. According toyet another embodiment of the invention the sieving coefficients formyoglobin under the same conditions are between 0.9 and 1.

The blood flow rates which can be used with devices comprising themembranes according to the invention are in the range of from 200 ml/minto 600 ml/min. Dialysate flow rates for use with the membranes accordingto the invention are in the range of from 300 ml/min to 1000 ml/min.Usually, blood flow rates of from 300 ml/min to 500 ml/min, dialysisflow rates of from 500 ml/min to 800 ml/min and UF rates of from 0 to 15ml/min will be used. For example, a standard flow rate used is Q_(B)=300m/mm, Q_(D)=500 ml/min and UF=0 ml/min.

Due to the combination of the housing design, the physical properties ofthe single fibers and of the fiber bundle with the new type of membranesaccording to the invention, the hemodialyzers of the invention areespecially beneficial for the treatment of chronic and acute renalfailure by hemodialysis, thereby achieving and even exceeding aperformance which can currently be achieved only in hemodiafiltrationtherapy. The new combined features allow the highly efficient removal ofuremic molecules ranging from small to large molecular weight (FIG. 1 )while efficiently retaining albumin and larger essential proteins. Stateof the art membranes at the most achieve a similar performance in HDFtreatment modes.

This becomes especially apparent when considering the clearanceperformance of the hemodialyzers of the invention. The clearance C(ml/min) refers to the volume of a solution from which a solute iscompletely removed per time unit. In contrast to the sieving coefficientwhich is the best way to describe the structure and performance of amembrane as the essential component of a hemodialyzer, clearance is ameasure of the overall dialyzer design and function and hence dialysiseffectiveness. The clearance performance of a dialyzer can be determinedaccording to DIN EN ISO8637:2014. Clearance therefore is used herein todescribe the excellent performance which can be achieved by using theaforementioned highly efficient membranes in a hemodialyzer as describedabove.

With a hemodialyzer according to the invention excellent clearance ratesas determined in vitro according to Example 4 with, for example, a Q_(B)between 200 ml/min and 500 ml/min, a Q_(D) of 500 ml/min and an UF of 0ml/min and an effective surface area of from 1.6 m² to 1.8 m² formolecules covering a broad range of uremic toxins of various molecularweights (see Table IV) can be achieved. Ultrafiltration rates may beincreased to about 20 ml/min or to 30 ml/min without departing from theinvention. Generally, ultrafiltration rates will be in the range of from0 to 20 ml/min or 0 to 15 ml/min, but can also be chosen to be 0 to 10ml/min or simply 0 ml/min. In general, clearance rates determined invitro according to DIN EN ISO8637:2014 at a Q_(B) between 200 ml/min and500 ml/min, a Q_(D) of 500 ml/min and an UF of 0 ml/min and an effectivesurface area of 1.7 m² to 1.8 m² for small molecular weight substancessuch as, for example, urea, are in the range of between 190 and 400ml/min can be achieved; such rates are superior, but at least equivalentto the current state of the art hemodialysis filters. The same is truefor clearance rates for other small molecules such as creatinine andphosphate, which are in the range of between 190 and 380 ml/min. Thus,the hemodialyzers according to the invention can achieve betterclearance rates for higher molecular weight blood components without adrop in clearance performance for small molecules, which is often thecase with hemodialyzers which have been described before. Clearancerates as determined according to DIN EN ISO8637:2014 at a Q_(B) between200 ml/min and 500 ml/min, a Q_(D) of 500 ml/min and an UF of 0 ml/minfor vitamin B₁₂, for example, are in the range of from 170 to 280ml/min, for inulin clearance rates of between 140 and 240 ml/min can beachieved, respectively. Clearance rates for myoglobin are in the rangeof between 110 and 200 ml/min. Clearance rates for cytochrome C asdetermined according to DIN EN ISO8637:2014 at a Q_(B) between 200 ml/mmand 500 ml/min, a Q_(D) of 500 ml/min and an UF of 0 ml/min (Tables VIthrough VIII) are in the range of between 130 and 200 ml/min. Forexample, cytochrome C clearance values of the hemodialyzer of theinvention as determined according to DIN EN ISO8637:2014 at a Q_(B)between 200 ml/min and 500 ml/min, a Q_(D) of 500 ml/min and an UF of 0ml/min are significantly higher than the corresponding values of stateof the art dialyzers used in hemodialysis therapy (see Table VI), andare even superior, under hemodialysis conditions, to the clearanceperformance of current state of the art hemodiafilters determined underHDF condition with increased ultrafiltration rates (Table VII). Thehemodialyzers according to the invention under hemodialysis conditions(for example, UF=0 ml/min) achieve values which are comparable to whatcan be achieved with state of the art hemodiafilters measured at highultrafiltration rates (Table VIII).

It will be readily apparent to one skilled in the art that varioussubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention.

The present invention will now be illustrated by way of non-limitingexamples in order to further facilitate the understanding of theinvention.

EXAMPLES Example 1

Preparation of Membranes

1.1 Membrane A

Two solutions were used for the formation of the membrane, the polymersolution consisting of hydrophobic and hydrophilic polymer componentsdissolved in N-methyl-pyrrolidone, and the center solution being amixture of N-methyl-pyrrolidone (NMP) and water. The polymer solutioncontained poly(aryl)ethersulfone (PAES 14.0 wt-%) andpolyvinylpyrrolidone (2 wt-% of PVP K85 and 5 wt-% of PVP K30, a totalPVP concentration in the polymer solution of 7 wt %). The solutionfurther contained NMP (77.0 wt-%) and water (2.0 wt-%). The viscosity ofthe polymer solution, measured at a temperature of 22° C., was between5500 and 5700 mPas. The spinneret was heated to a temperature of 59° C.The center solution contained water (54.5 wt-%) and NMP (45.5 wt-%). Adefined and constant temperature regime was applied to support theprocess. The center solution was pre-heated to 59° C. and pumped towardsthe two-component hollow fiber spinneret. The polymer solution wasleaving the spinneret through an annular slit with an outer diameter of500 mm and an inner diameter of 350 mm/center solution slit 180 mm. Thecenter fluid was leaving the spinneret in the center of the annularpolymer solution tube in order to start the precipitation of the polymersolution from the inside and to determine the inner diameter of thehollow fiber. The two components (polymer solution and center fluid)were entering a space separated from the room atmosphere at the sametime. This space is referred to as spinning shaft. A mixture of steam(˜100° C.) and air (22° C.) was injected into the spinning shaft. Thetemperature in the spinning shaft was adjusted by the ratio of steam andair to 56° C. The length of the spinning shaft was 1050 mm. By the aidof gravity and a motor-driven roller, the hollow fiber was drawn fromtop to bottom, from spinneret through the spinning shaft into a waterbath. The water bath had a temperature of 25° C. The spinning velocitywas about 45 m/min. The hollow fiber was subsequently led through acascade of water baths with temperatures increasing from 25° C. to 76°C. The wet hollow fiber membrane leaving the water-rinsing bath wasdried in a consecutive online drying step. The hollow fiber wascollected on a spinning wheel in the shape of a bundle. In some batchesan additional texturizing step was added before the bundle was prepared.Alternatively, hand bundles according to Example 2 were formed forfurther experiments (see also Examples 3 and 4). Scanning micrographs ofthe outer surface and of the hollow fiber according to Example 1.1 areshown in FIG. 8 . The membrane has a finger-like structure. The innerdiameter of Membrane A was adjusted to be 180 μm and the wall thicknesswas chosen to be 35 μm.

1.2 Membrane B

Membrane B is based on the same polymer solution and center solution asMembrane A of Example 1.1 and was produced in analogy to what isdescribed there. Differences were introduced only with regard to thetemperature of the spinneret, which was adjusted to 58° C., thetemperature of the spinning shaft, which was adjusted to 55° C. Thetemperature of the center solution was adjusted to 58° C. via thespinning nozzle.

1.3 Membrane C

Membrane C is based on the same polymer solution and center solution asMembrane A of Example 1.1 and was produced in analogy to what isdescribed there. Differences were introduced only with regard to thetemperature of the spinneret, which was adjusted to 57° C., and thetemperature of the spinning shaft, which was adjusted to 54° C. Thetemperature of the center solution was adjusted to 57° C. via thespinning nozzle.

1.4 Membrane D

Membrane D is based on the same polymer solution and center solution asin Example 1.1 and was produced in analogy to what is described there.Differences were introduced only with regard to the polymer viscositywhich in this case was 5071 mPas. The temperature of the center fluidwas according to the spinning nozzle.

1.7 Membrane E

Membrane E is based on the same polymer solution and center solution asdescribed in Example 1.1 and was produced in analogy to what isdescribed there. In this case, the sieving data obtained slightly variedfrom data obtained with membranes prepared according to Example 1.1.

1.6 Membrane F

For obtaining sponge-like membrane structures, the polymer solution incontrast to Examples 1.1 to 1.5 contained a slightly differentcomposition but was otherwise produced in analogy to what is describedin Example 1.1. The solution contained poly(aryl)ethersulfone (PAES 14.0wt-%) and polyvinylpyrrolidone (2 wt-% of PVP K85 and 5 wt-% of PVPK30). The solution further contained NMP (73.0 wt-%) and water (6.0wt-%). The spinneret was heated to a temperature of 57° C. The centersolution contained water (49.0 wt-%) and NMP (51.0 wt-%). The centersolution was kept at 57° C. The temperature in the spinning shaft wasadjusted to 55° C. The length of the spinning shaft was 1000 mm. Thespinning velocity was 45 m/min. Scanning micrographs of the outersurface and of the hollow fiber according to Example 1.6 are shown inFIG. 9 . The inner diameter of Membrane F was again adjusted to be 180μm and the wall thickness was again chosen to be 35 μm.

1.7 Membrane G

Membrane G was based on the same polymer solution as described inExample 1.6 (Membrane F) and was produced in analogy to what isdescribed there. Differences were introduced with regard to thetemperature of the spinneret, which was adjusted to 58° C., and thetemperature of the spinning shaft, which was adjusted to 56° C. Thetemperature of the center solution was adjusted to 58° C. via thespinning nozzle. The inner diameter of Membrane G was again adjusted tobe 180 μm and the wall thickness was again chosen to be 35 μm.

1.8 Comparative Example: High Cut-Off Membrane β

The polymer solution used for preparing a high cut-off Membrane β (seeFIG. 2 ) according to the prior art was identical to the polymersolution used for the preparation of Membrane A (Example 1.1). However,the center solution used contained 53.0 wt.-% water and 47.0 wt.-% NMP.During the membrane formation process polymer and center solution werebrought in contact with a spinneret and the membrane precipitated. Thespinning velocity was 45 m/min. A defined and constant temperatureregime was applied to support the process, wherein the spinneret waskept at a temperature of 58° C. The precipitated hollow fiber fellthrough a spinning shaft having a height of 1050 mm which was filledwith steam (>99% relative humidity). The temperature within the shaftwas stabilized to 54° C. Finally, the fiber entered a washing bathcontaining about 4 wt-% NMP in water, wherein the bath was kept atemperature of 20° C. The membrane was further washed in two additionalwater baths (75° C. and 65° C.) with counter current flow (250 l/h).Membrane drying was performed online, wherein remaining water wasremoved. The fibers had an inner diameter of 215 μm and a wall thicknessof 50 μm.

1.9 Comparative Example: High Cut-Off Membrane α

The polymer solution and center solution as well as the process used forpreparing the high cut-off Membrane α according to the prior art wasidentical to the polymer solution used for the preparation of Membrane β(Example 1.8). Differences existed with regard to the spinning velocity,which was lower than in Example 1.8 (29 m/min) and the online dryingstep, which in this case was omitted.

1.10 Comparative Example: High Cut-Off Membrane γ

The polymer solution and center solution as well as the process used forpreparing the high cut-off Membrane γ according to the prior art wasidentical to the polymer solution used for the preparation of Membrane β(Example 1.8). Differences were introduced with regard to spinningvelocity (34 m/min) and with regard to the temperature of the spinningshaft (56° C.).

1.11 Comparative Example: High Cut-Off Membrane ϕ

Membrane ϕ (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a Phylther® hemodialyzer (Phylther® HF 22 SD (2.2 m²,Bellco, Italy)). The hollow fiber membranes are based on polyphenylene.The hollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.12 Comparative Example: High-Flux Membrane 1

Membrane 1 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a PES-21Dα^(eco) hemodialyzer (Nipro, Japan). The hollowfiber membranes are polyethersulfone based membranes (Polynephron®). Thehollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.13 Comparative Example: High-Flux Membrane 2

Membrane 2 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an APS 21EA hemodialyzer (2.1 m², Asahi Kasei MedicalCo., Ltd.). The hollow fiber membranes are polysulfone based membraneswith a wall thickness of 45 μm and an inner diameter of 180 μm. Thehollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.14 Comparative Example: High-Flux Membrane 3

Membrane 3 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a Phylther® HF 17 G (1.7 m², Bellco, Italy)). The hollowfiber membranes are based on polyphenylene. The hollow fibers were usedfor preparing standardized mini-modules according to Example 2 forfurther tests.

1.15 Comparative Example: High-Flux Membrane 4

Membrane 4 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a FX-S 220 filter (2.2 m², Fresenius Medical Care JapanKK) which is based on polysulfone and has a wall thickness of 35 μm andan inner diameter of 185 μm. The hollow fibers were used for preparingstandardized mini-modules according to Example 2 for further tests.

1.16 Comparative Example: High-Flux Membrane 5

Membrane 5 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an Optiflux® F180NR filter (1.8 m², Fresenius MedicalCare North America) which is based on polysulfone and has a wallthickness of 40 μm and an inner diameter of 200 μm. The hollow fiberswere used for preparing standardized mini-modules according to Example 3for further tests.

1.17 Comparative Example: High-Flux Membrane 6

Membrane 6 (FIG. 2 ) refers to hollow fiber membranes which wereprepared in accordance with Example 1 of EP 2 113 298 A1. Thetemperatures of the spinneret and the spinning shaft were chosen to be56° C. and 53° C., respectively, and the height of the spinning shaftwas adjusted to the same heights as chosen in Example 1.1. Thetemperature of the water bath was adjusted to 20° C. The hollow fiberswere assembled in standardized mini-modules according to Example 2 forfurther tests.

1.18 Comparative Example: High-Flux Membrane 7

Membrane 7 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an FDY-210GW filter (2.1 m² from Nikkiso Co., LTD.) whichcomprises a so-called PEPA@ membrane (Polyester-Polymer Alloy, with PVP)having a wall thickness of 30 μm and an inner diameter of 210 μm. Thedialyzer was developed for applications that require an extended sievingcoefficient profile. The hollow fibers were used for preparingstandardized mini-modules according to Example 2 for further tests.

1.19 Comparative Example: High-Flux Membrane 8

Membrane 8 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an FDY-21GW filter (2.1 m² from Nikkiso Co., LTD.) whichcomprises a so-called PEPA® membrane (Polyester-Polymer Alloy) having awall thickness of 30 μm and an inner diameter of 210 μm. The hollowfibers were used for preparing standardized mini-modules according toExample 2 for further tests.

1.20 Comparative Example: High-Flux Membrane 9

Membrane 9 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an FLX-21 GW filter (2.1 m² from Nikkiso Co., LTD.,PVP-free) which comprises a so-called PEPA® membrane (Polyester-PolymerAlloy) having a wall thickness of 30 μm and an inner diameter of 210 μm.The hollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.21 Comparative Example: High-Flux Membrane 10

Membrane 10 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a PES-21 SEα^(eco) hemodialyzer (Nipro, Japan). Thehollow fiber membranes are polyethersulfone based membranes. The hollowfibers were used for preparing standardized mini-modules according toExample 2 for further tests.

1.22 Comparative Example: High-Flux Membrane 11

Membrane 11 (FIG. 2 ) refers to hollow fiber membranes as used inPolyflux® 170H filters (1.7 m², Gambro Lundia AB) which are based on ablend of polyarylethersulfone (PAES), polyvinylpyrrolidone (PVP) andpolyamide and have a wall thickness of 50 μm and an inner diameter of215 μm. The hollow fibers were assembled in standardized mini-modulesaccording to Example 2 for further tests.

1.23 Comparative Example: High-Flux Membrane 12

Membrane 12 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an EMiC®2 filter (1.8 m² from Fresenius Medical CareDeutschland GmbH). The respective hollow fibers are based on polysulfoneand have a wall thickness of 35 μm and an inner diameter of 220 μm. Thehollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.24 Comparative Example: High-Flux Membrane 13

Membrane 13 (FIG. 2 ) refers to hollow fiber membranes which wereextracted from a PES-21 Sα^(eco) hemodialyzer (Nipro, Japan). The hollowfiber membranes are polyethersulfone based membranes. The hollow fiberswere used for preparing standardized mini-modules according to Example 2for further tests.

1.25 Comparative Example: Low-Flux Membrane a

Membrane a (FIG. 2 ) refers to hollow fiber membranes as used inPolyflux® 21L filters (2.1 m², Gambro Lundia AB) which are based on ablend of polyarylethersulfone (PAES), polyvinylpyrrolidone (PVP) andpolyamide and have a wall thickness of 50 μm and an inner diameter of215 μm. The hollow fibers were assembled in standardized mini-modulesaccording to Example 2 for further tests.

1.26 Comparative Example: Low-Flux Membrane b

Membrane b (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an APS 21E hemodialyzer (2.1 m², Asahi Kasei Medical Co.,Ltd.). The hollow fiber membranes are polysulfone based membranes with awall thickness of 45 μm and an inner diameter of 200 μm. The hollowfibers were used for preparing standardized mini-modules according toExample 2 for further tests.

1.27 Comparative Example: Low-Flux Membrane c

Membrane c (FIG. 2 ) refers to hollow fiber membranes which wereextracted from an APS 21EL hemodialyzer (2.1 m², Asahi Kasei MedicalCo., Ltd.). The hollow fiber membranes are polysulfone based membraneswith a wall thickness of 45 μm and an inner diameter of 200 μm. Thehollow fibers were used for preparing standardized mini-modulesaccording to Example 2 for further tests.

1.28 Comparative Example: Protein Leaking Membrane

The protein leaking membrane (FIG. 2 , (▾)) refers to hollow fibermembranes which were extracted from an Filtryzer BK-1.6F filter (1.6 m²from Toray Industries, Inc.) which comprises a so-called PMMA membrane(poly(methyl methacrylate)) having a wall thickness of 30 μm and aninner diameter of 210 μm. The hollow fibers were used for preparingstandardized mini-modules according to Example 2 for further tests.

Example 2

Preparation of Filters, Hand Bundles and Mini-Modules; Measurement ofSieving Coefficients

2.1 Preparation of Filter, Hand-Bundles and Mini-Modules

Filters can be prepared by introducing a fiber bundle into a dialyserhousing. The bundle is potted with polyurethane, ends are cut, on bothsides of the dialyser a header is fixed to the housing, the dialyser isrinsed with hot water and dried with air. During this last drying step,a certain amount of about between 10 g and 30 g of residual water per m²effective membrane area is left on the dialyser. After labelling andpackaging, the dialyser can be steamsterilized within the packaging inan autoclave at 121° C. for at least 21 min.

The preparation of a hand bundle after the spinning process is necessaryto prepare the fiber bundle for following performance tests withmini-modules. The first process step is to cut the fiber bundles to adefined length of 23 cm. The next process step consists of melting theends of the fibers. An optical control ensures that all fibers are wellmelted. Then, the ends of the fiber bundle are transferred into apotting cap. The potting cap is fixed mechanically and a potting tube isput over the potting caps. Then the fibers are potted with polyurethane.After the polyurethane has hardened, the potted membrane bundle is cutto a defined length and stored dry.

Mini-modules (fiber bundles in a housing) are prepared in a similarmanner. The mini-modules ensure protection of the fibers and can be usedfor steam-sterilization. The manufacturing of the mini-modules comprisesthe following specific steps:

-   -   (A) The number of fibers required is calculated for a nominal        surface A of 360 cm² according to the following equation:        A=π×d _(i) ×l×n,        -   wherein d_(i) is the inner diameter of fiber [cm], n            represents the amount of fibers, and 1 represents the fiber            length in the housing (17 cm).    -   (B) The fiber bundle is cut to a defined length.    -   (C) The fiber bundle is transferred into the housing before the        melting process.        2.2 Albumin, β2-M and Myoglobin Sieving Coefficients

Middle molecules, consisting mostly of peptides and small proteins withmolecular weights in the range of 500-60,000 Da, accumulate in renalfailure and contribute to the uremic toxic state. Beta2-microglobulin(beta2-MG or β2-M) with a molecular weight of 11,000 is consideredrepresentative of these middle molecules. Myoglobin has a molecularweight (MW) of about 17 kDaa is already larger and will not be clearedfrom blood to the same extend by known high-flux dialyzers, whereas itis readily removed by high cut-off dialyzers. Finally, albumin with a MWof about 67 kDaa is a key element in describing the sievingcharacteristics of membranes, as albumin should not be allowed to pass amembrane for chronic hemodialysis to a significant extent. The sievingcoefficients for said proteins were determined for Membrane A accordingto the invention, Membrane 78, and for Membrane β according to EN1283(Q_(B)max, UF=20%) in bovine plasma at with Q_(B)=600 ml/min and UF=120ml/min. Further measurements were carried out at Q_(B)=400 ml/min andUF=25 ml/min according to DIN EN ISO8637:2014. The bovine plasma usedhad a total protein concentration of 60±2 g/l. Myoglobin from horseheart (M1882) was purchased from Sigma-Aldrich Co. LLC. Purified β2-M(PHP135) was obtained from Bio-Rad AbD Serotec GmbH or Lee Bio Solutions(St Louis, Mo., U.S.A.) and diluted in bovine plasma. The resulting testsolutions had the following final concentrations: albumin as containedin the bovine plasma, myoglobin (100 mg/l), β2-M (3 mg/l). The testsolutions were gently stirred at 37±1° C. Mini-modules as described inExample 2.1 were primed with 0.9% NaCl solution. The setup for the testwas according to ISO 8637:2014. The final protein concentration of thetest solution was 60±5 g/l.

Example 3

Dextran Sieving Measurements

3.1 Dextran Solutions

Fractions of dextran supplied by Fluka (Mw 6, 15-20, 40, 70, 100, 200,500 kDaa) and Sigma-Aldrich (Mw 9-11 kDaa) (both from Sigma-Aldrich Co.LLC, St. Louis, USA) were used without further purification. Solutionsof dextrans with the different molecular weight fractions were combinedin Millipore water (i.e., Type 1 ultrapure water, as defined by ISO3696) at a concentration of 1 g/l for each fraction, which results in anoverall concentration of 8 g/l.

3.2 Devices and Sample Preparation

For characterizing the membranes according to the invention andcomparing them with membranes known from the prior art, it was necessaryto eliminate the differences between devices caused by having differentmembrane surface areas or fiber numbers. Therefore, standardizedmini-modules with a surface area of from 280 cm² to 300 cm² weremanufactured from the membranes according to the invention or frommembranes according to the prior art. In cases where the prior artmembranes were part of complete filter devices, the membrane wasextracted from said devices and mini-modules were prepared therefrom.Each mini-module had a nominal length of 170 mm, an effective length ofapprox. 120 mm to 150 mm (without PU potting) and an inner diameter of10 mm. The internal diameter of fibers ranged between 170 μm and 220 μm,and the wall thickness between 30 μm and 50 μm (depending on thespecific membranes used, see Examples 1.1-1.28 for details). Hence, thepacking density also varied between 23% and 31%. All mini-modules wereimmersed in water for 30 min before the filtration experiments.Mini-modules to be characterized after contact with blood first have tobe perfused with blood (bovine, 32% of hematocrits, 60 g/l of proteincontent and 1600 units/l of heparin) for 40 min and rinsed afterwardswith water for 30 to 60 min, as proposed elsewhere (Kunas GA, Burke RA,Brierton MA, Ofsthun NJ. The effect of blood contact and reuse on thetransport properties of high-flux dialysis membranes. ASAIO J. 1996;42(4):288-294).

3.3 Dextran Sieving Coefficient Tests

Filtration experiments were carried out under a constant shear rate(γ=750s⁻¹) and with the ultrafiltration rate set at 20% of the bloodside entrance flux Q_(Bin), calculated as:

$Q_{Bin} = \frac{\gamma \cdot n \cdot \pi \cdot d_{i}^{3} \cdot 60}{32}$where Q_(Bin) is the flux at the blood side entrance in ml/min; n is thenumber of fibers in the minimodule; d_(i) is the inner diameter of thefibers in cm and γ is the constant shear rate mentioned above. A schemeof the experimental setup is shown in FIG. 3 . As can be seen, thefiltration conditions are without backfiltration, contrary to theconditions typical of hemodialysis. Additionally, the chosen conditionsassure a filtration regime since the Peclet-number for all theinvestigated membranes is well above 3 even for molecules in the 0.1kDaa to 1 kDaa range. The dextran solution was recirculated at 37° C.±1°C. Feed (blood side entrance), retentate (blood side exit), and filtrate(dialysate exit) samples were taken after 15 min. Relative concentrationand molecular weight of the samples were analyzed via gel permeationchromatography. The analysis was carried out in a High PerformanceLiquid Chromatography (HPLC) device (HP 1090A or Agilent 1200; Agilent,Santa Clara, Calif., USA) equipped with an RI detector (G1362 fromAgilent) and TSKgel columns (PWXL-Guard Column, G 3000 PWXL, G 4000PWXL; Tosoh, Tessenderlo, Belgium). Samples were filtered through a 0.45μm filter type OE67 from Schleicher and Schnell, Einbeck, Germany.Calibration was done against dextran standards (Fluka). The sievingcoefficient SC is calculated according to the equation as follows:

${SC} = \frac{2 \cdot c_{F}}{c_{P} + c_{R}}$where c_(F) is the concentration of the solute in the filtrate, c_(P)its concentration in the permeate and c_(R) its concentration in theretentate.3.4 Results of the Dextran Sieving Coefficient Tests

TABLE III MWCO and MWRO values Average MWRO MWCO Membrane (90%) (10%)Membrane Classification MW [D] MW [D] Membrane A¹⁾ (Ex. 1.1) Invention11.700 75.000 Membrane B²⁾ (Ex. 1.2) Invention 10.700 80.000 MembraneC³⁾ (Ex. 1.3) Invention 9.500 70.000 Membrane D (Ex. 1.4) Invention11.600 88.000 Membrane E (Ex. 1.5) Invention 11.700 90.000 Membrane F(Ex. 1.6) Invention 11.921 105.000 Membrane G (Ex. 1.7) Invention 10.22371.000 Comparative Example High cut- 15.000 300.000 Membrane β (Ex. 1.8)off Comparative Example High cut- 19.300 200.000 Membrane α (Ex. 1.9)off Comparative Example High cut- 17.000 300.000 Membrane γ (Ex. 1.10)off Comparative Example High cut- 12.020 150.000 Membrane ϕ (Ex. 1.11)off Comparative Example High-flux 9.700 50.500 Membrane 1 (Ex. 1.12)Comparative Example High-flux 6.600 33.000 Membrane 2 (Ex. 1.13)Comparative Example High-flux 7.300 67.000 Membrane 3 (Ex. 1.14)Comparative Example High-flux 5.800 28.000 Membrane 4 (Ex. 1.15)Comparative Example High-flux 4.400 18.900 Membrane 5 (Ex. 1.16)Comparative Example High-flux 5.300 43.000 Membrane 6 (Ex. 1.17)Comparative Example High-flux 8.300 30.000 Membrane 7 (Ex. 1.18)Comparative Example High-flux 7.000 32.600 Membrane 8 (Ex. 1.19)Comparative Example High-flux 5.800 58.000 Membrane 9 (Ex. 1.20)Comparative Example High-flux 8.300 45.000 Membrane 10 (Ex. 1.21)Comparative Example High-flux 5.900 50.000 Membrane 11 (Ex. 1.22)Comparative Example High-flux 7.300 40.000 Membrane 12 (Ex. 1.23)Comparative Example High-flux 8.700 58.000 Membrane 13 (Ex. 1.24)Comparative Example Low-flux 2.200 19.000 Membrane a (Ex. 1.25)Comparative Example Low-flux 3.060 13.000 Membrane b (Ex. 1.26)Comparative Example Low-flux 2.790 10.000 Membrane c (Ex. 1.27)Comparative Example Protein 3.000 67.000 Protein Leaking Mem- Leakingbrane (Ex. 1.28) ¹⁾Stokes-Einstein pore radius, based on dextran sievingexperiments before blood contact: 6.5 ± 0.2 nm ²⁾Stokes-Einstein poreradius, based on dextran sieving experiments before blood contact:: 6.0± 0.3 nm ³⁾Stokes-Einstein pore radius, based on dextran sievingexperiments before blood contact:: 5.4 ± 0.1 nm

Example 4

Clearance Performance

The clearance C (ml/min) refers to the volume of a solution from which asolute is completely removed per unit time. In contrast to the sievingcoefficient which is the best way to describe a membrane as theessential component of a hemodialyzer, clearance is a measure of theoverall dialyzer function and hence dialysis effectiveness. If notindicated otherwise, the clearance performance of a dialyzer wasdetermined according to ISO 8637:2004(E). The set-up of the test circuitwas as shown in FIG. 4 of ISO 8637:2004(E). Flows are operated in singlepath.

Filters were prepared from Membrane A with an effective surface area of1.7 m² (12996 fibers, all ondulated) and compared with a filter preparedfrom a high cut-off membrane, Membrane β (2.1 m², all ondulated), with afilter prepared from a standard high-flux membrane, Membrane 6 (1.8 m²,all ondulated) (Table V), and with high-flux dialyzers FX_(CorDiax)80(1.8 m²) and FX_(CorDiax)100 (2.2 m²) (Table VI), both from FreseniusMedical Care Deutschland GmbH. Comparison of said filters was done inhemodialysis mode.

Membrane A was also compared with Nephros OLpūr™ MD 190, Nephros OLpūr™MD 220 (1.9 m² and 2.2. m², respectively, both from Nephros Inc. U.S.A.)and FX CorDiax Heamodiafilters FX_(CorDiax)800 and FX_(CorDiax)1000,wherein clearance values for the Nephros and FX filters were determinedin hemodiafiltration mode (see Tables VII and VIII) in order to compareoutcomes for the membrane according to the invention in hemodialysismode with the outcome of filters designed for HDF in hemodiafiltrationmode.

In each case, the blood compartment of the tested device was perfusedwith dialysis fluid containing one or more of the test substances asindicated in Table IV. The dialysate compartment was perfused withdialysate.

TABLE IV Concentration of test substances in the test solutions used fordetermining clearance rates Test Substance (MW [Da]) Concentration Urea(60) 17 mmol/l Creatinine (113) 884 μmol/l Phosphate (132) 3.16 mmol/lVitamin B12 (1355) 37 μmol/l Inulin (5200) 0.10 g/l Cytochrome C (12230)0.03 g/l Myoglobin (17000) 6 μmol/l

Stable blood and dialysate flow rates were established as indicated inthe respective examples shown in Tables V, VI, VII and VIII. Temperature(37° C.±1), pressures and ultrafiltration rates were also kept stable asindicated. Test samples were collected not earlier than 10 minutes aftera steady state had been reached. The samples were analyzed and theclearance was calculated according to formula (I).

$\begin{matrix}{C = {{\frac{C_{Bin} - C_{Bout}}{C_{Bin}}Q_{Bin}} + {\frac{C_{Bout}}{C_{Bout}}Q_{F}}}} & (I)\end{matrix}$where

-   C_(Bin) is the concentration of solute on the blood inlet side of    the hemodialyser;-   C_(Bout) is the concentration of solute on the blood outlet side of    the hemodialyser;-   Q_(Bin) is the blood flow rate at the inlet of the device; and-   Q_(F) is the filtrate flow rate (ultrafiltration rate).

TABLE V Clearance performance of hemodialyzers according to theinvention (based on Membrane A) in comparison with hemodialyzers of theprior art (hemodialysis mode) Q_(D) = 500 ml/min Q_(D) = 500 ml/minClear- Membrane 6 Membrane β Membrane A fil- ance filter device filterdevice ter device (mL/min) (1.8 m² (2.2 m² (1.7 m² in vitro UF = 0ml/min) UF = 0 ml/min) UF = 0 ml/min) QB [ml/min] Urea 200 198 199 199300 281 286 286 400 338 349 351 500 375 390 396 QB [ml/min] Creatinine200 195 196 196 300 267 273 273 400 315 326 329 500 348 361 369 QB[ml/min] Phosphate 200 191 195 194 300 255 269 269 400 297 320 322 500326 354 360 QB [ml/min] Vitamin B₁₂ 200 158 175 170 300 191 221 216 400213 252 249 500 228 274 276 QB [ml/min] Inulin 200 — 157 141 300 — 191171 400 — 214 194 500 — 230 213 QB [ml/min] Myoglobin 200 — 126 118 300— 146 140 400 — 160 157 500 — 170 172

TABLE VI Clearance performance of hemodialyzers according to theinvention (based on Membrane A) in comparison with hemodialyzers of theprior art (hemodialysis mode) Q_(D) = 500 ml/min Q_(D) = 500 ml/minMembrane A Clearance FX_(CorDiax)80 FX_(CorDiax)100 filter device(ml/min) (1.8 m² (2.2 m² (1.7 m² in vitro UF = 0 ml/min) UF = 0 ml/min)UF = 0 ml/min) QB [ml/min] Urea 200 — — 199 300 280 283 286 400 336 341351 500 — — 396 QB [ml/min] Creatinine 200 — — 196 300 261 272 273 400303 321 329 500 — — 369 QB [ml/min] Phosphate 200 — — 194 300 248 258269 400 285 299 322 500 — — 360 QB [ml/min] Vitamin B₁₂ 200 — — 170 300190 207 216 400 209 229 249 500 — — 276 QB [ml/min] Cytochrome C 200 — —133 300 111 125 160 400 117 133 180 500 — — 197

TABLE VII Clearance performance of hemodialyzers according to theinvention (based on Membrane A) in hemodialysis mode in comparison withhemodiafilters of the prior art (he-modiafiltration mode) Q_(D) = 500ml/min Q_(D) = 500 ml/min FX_(CorDiax)800 FX_(CorDiax)1000 UF = 0 ml/min(2.0 m² (2.3 m² Membrane A Clearance UF = 75 mL/min* UF = 75 mL/min*filter device (ml/min) UF = 100 UF = 100 (1.7 m² in vitro mL/min^(#))mL/min^(#)) UF = 0 ml/min) QB [ml/min] Urea 200 — — 199 300  291*  292*286 400  365^(#)  367^(#) 351 500 — — 396 QB [ml/min] Creatinine 200 — —196 300 277 280 273 400 339 343 329 500 — — 369 QB [ml/min] Phosphate200 — — 194 300 267 271 269 400 321 328 322 500 — — 360 QB [ml/min]Vitamin B12 200 — — 170 300  217*  225* 216 400  251^(#)  262^(#) 249500 — — 276 QB [ml/min] Cytochrome C 200 — — 133 300 141 151 160 400 160172 180 500 — — 197

TABLE VIII Clearance performance of hemodialyzers according to theinvention (based on Membranes A and B) in hemodialysis mode incomparison with hemodiafilters of the prior art (hemodiafiltration mode)Q_(D) = 500 Q_(D) = 500 Q_(D) = 500 ml/min ml/min, ml/min NephrosNephros Membrane Membrane OLpūrTM OLpūrTM A filter B filter MD 190 MD220 device device Clearance (1.9 m² (2.2 m² (1.7 m² (2.0 m² (mL/min) UF= 200 UF = 200 UF = 0 UF = 0 in vitro ml/min) ml/min) ml/min) ml/min) QB[ml/min] Urea 200 198 199 199 — 300 276 291 286 — 400 332 364 351 360**500 353 424 396 — QB [ml/min] Creatinine 200 196 198 196 — 300 264 279273 — 400 311 348 329 — 500 331 403 369 — QB [ml/min] Phosphate 200 194196 194 — 300 257 272 269 — 400 300 336 322 — 500 318 383 360 — QB[ml/min] Vitamin B12 200 191 192 170 — 300 221 247 216 — 400 242 292 249260** 500 251 323 276 — QB [ml/min] Cytochrome C 200 158 161 133 — 300179 203 160 — 400 193 237 180 — 500 200 256 197 — **constructed value

Example 5

Determination of Albumin Loss in a Simulated Treatment

The simulated treatment is performed, for example, with a AK 200™ Sdialysis machine. During the treatment samples of 1 ml are secured fromthe dialysate side of the system after 15, 30, 45, 60, 90, 120, 150,180, 210 and 240 minutes and the albumin concentration in the samples inmg/l is determined (BSA, Bovine Serum Alubmin). Albumin loss iscalculated with the help of SigmaPlot software by establishing aregression curve of the type f(x)=y_(o)+ae^(-bx). The albumin loss canbe calculated by integration of the regression curve, F_((x)) from 0 to240 mintues, i.e. F(x)=bxy_(o)−ae^(-bx). The simulated treatment iscarried out as follows. A bag with 0.9% NaCl (500 ml) is connected tothe dialysis monitor. The blood pump is started and the test filter isrinsed at Q_(B)=100 ml/min, Q_(D)=700 ml/min, UF=0.1 ml/min with thesaid sodium chloride solution. Afterwards, the dialyzer is filled byusing the prescribed dialysate flow. The bovine blood (5000±50 ml) isprovided in a container and placed in a water bath at 38±1° C. 5 ml ofheparin are added in the beginning and then every hour. The blood iscarefully stirred throughout the treatment. The test can be run in HD orHDF mode. Standard parameters are Q_(B)=400 ml/min, Q_(D)=500 ml/min,UF=10. In case UF is >0 ml/min substitution fluid has to be used. Bloodflow, dialysate flow and UF rate are started and samples are taken fromthe dialysate side at the respective times. Albumin concentration in thesamples can be determined according to known methods.

The invention claimed is:
 1. A method of performing hemodialysis on apatient, said method comprising the step of contacting blood of thepatient with a hemodialyzer comprising a bundle of hollow fibermembranes comprising i) at least one hydrophobic polymer component andii) at least one hydrophilic polymer component, wherein the membrane hasa molecular retention onset (MWRO) of between 9.0 kDa and 14.0 kDa and amolecular weight cut-off (MWCO) of between 55 kDa and 130 kDa asdetermined by dextran sieving before blood contact of the membrane,wherein the membrane is configured for retention of albumin.
 2. Themethod of claim 1, wherein the patient is a patient with acute renalfailure.
 3. The method of claim 1, wherein the patient is a patient withchronic renal failure.
 4. The method of claim 1, wherein the method isperformed at a blood flow rate (QB) in the range of from 200 ml/min to600 ml/min.
 5. The method of claim 1, wherein the method is performed ata dialysate flow rate (QD) in the range of from 300 ml/min to 1000ml/min.
 6. The method of claim 1, wherein the method is performed at anultrafiltration flow rate (UF) in the range of from 0 to 30 ml/min. 7.The method of claim 1, wherein the method is performed at anultrafiltration flow rate (UF) in the range of from 0 to 15 ml/min. 8.The method of claim 1, wherein the membrane provides an effectivesurface area in the range of from 1.1 m² to 2.5 m².
 9. The method ofclaim 1, wherein the membrane provides an effective surface area in therange of 1.7 m².
 10. The method of claim 1, wherein the hemodialyzercomprises a packing density in the range of from 50% to 65%.
 11. Themethod of claim 1, wherein the hemodialyzer comprises 80% to 95% crimpedfibers and of 5% to 15% non-crimped fibers, relative to the total numberof fibers in the bundle.
 12. The method of claim 1, wherein thehemodialyzer comprises 86% to 94% crimped fibers and of 6% to 14%non-crimped fibers, relative to the total number of fibers in thebundle.
 13. The method of claim 1, wherein the hemodialyzer comprises86% to 92% crimped fibers and of 8% to 14% non-crimped fibers, relativeto the total number of fibers in the bundle.
 14. The method of claim 1,wherein the method is performed at a QB between 200 ml/min and 500ml/min, a QD of 500 ml/min and an UF of 0 ml/min, and wherein the methodprovides a clearance rate of urea in the range of from between 190ml/min and 400 ml/min, wherein the clearance rate is determined in vitroaccording to DIN EN ISO8637:2014.
 15. The method of claim 1, wherein themethod is performed at a QB between 200 ml/min and 500 ml/min, a QD of500 ml/min and an UF of 0 ml/min, and wherein the method provides aclearance rate of creatinine in the range of from between 190 ml/min and380 ml/min, wherein the clearance rate is determined in vitro accordingto DIN EN ISO8637:2014.
 16. The method of claim 1, wherein the method isperformed at a QB between 200 ml/min and 500 ml/min, a QD of 500 ml/minand an UF of 0 ml/min, and wherein the method provides a clearance rateof phosphate in the range of from between 190 ml/min and 380 ml/min,wherein the clearance rate is determined in vitro according to DIN ENISO8637:2014.
 17. The method of claim 1, wherein the method is performedat a QB between 200 ml/min and 500 ml/min, a QD of 500 ml/min and an UFof 0 ml/min, and wherein the method provides a clearance rate of vitaminB12 in the range of from between 170 ml/min and 280 ml/min, wherein theclearance rate is determined in vitro according to DIN EN ISO8637:2014.18. The method of claim 1, wherein the method is performed at a QBbetween 200 ml/min and 500 ml/min, a QD of 500 ml/min and an UF of 0ml/min, and wherein the method provides a clearance rate of inulin inthe range of from between 140 ml/min and 240 ml/min, wherein theclearance rate is determined in vitro according to DIN EN ISO8637:2014.19. The method of claim 1, wherein the method is performed at a QBbetween 200 ml/min and 500 ml/min, a QD of 500 ml/min and an UF of 0ml/min, and wherein the method provides a clearance rate of myoglobin inthe range of from between 110 ml/min and 200 ml/min, wherein theclearance rate is determined in vitro according to DIN EN ISO8637:2014.20. The method of claim 1, wherein the method is performed at a QBbetween 200 ml/min and 500 ml/min, a QD of 500 ml/min and an UF of 0ml/min, and wherein the method provides a clearance rate of cytochrome Cin the range of from between 130 ml/min and 200 ml/min, wherein theclearance rate is determined in vitro according to DIN EN ISO8637:2014.